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Cognitive Impairment, HCV, HIV & Meth
"Risk of Cognitive Impairment High in HCV-HIV Coinfection and Methamphetamine Addiction"
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Study authors find:
".....The current study adds to evidence that HCV infection has implications for brain functioning.....HCV infection has an independent adverse effect on NP performance and that the effects of HCV, HIV, and METH use are additive....In a sample of polysubstance users, investigators found slower reaction time on a modified Stroop task among HCV+ subjects, relative to HIV+ subjects, with coinfected individuals performing worst...Because hepatitis C is potentially curable, its identification and treatment are likely to result in improved neurobehavioral outcomes among individuals with HIV infection and substance use disorders....." See Author Discussion following Reuters report.
NEW YORK (Reuters Health) May 06 - Coinfection with hepatitis C virus (HCV) increases the neuropsychological deficits observed in patients with HIV infection and methamphetamine dependence, according to an article in the April 26th issue of Neurology.
After starting a study of the effects of HIV and meth addiction on cognitive function, Dr. M. Cherner and colleagues at the University of California San Diego found that many of the 430 study participants were also infected with HCV. They therefore investigated the effect of HCV comorbidity on outcomes of neuropsychological testing.
Included were 190 subjects with one of the three risk factors, 110 with two and 40 with three, along with 90 normal control subjects. HCV infection was most prevalent in those who were HIV-positive and methamphetamine-positive (37%) and lowest among those negative for both factors (2%).
The prevalence of global impairment increased with the number of risk factors (p < 0.0001). There were also additive effects on the individual domains of learning, motor speed and dexterity, delayed recall, and abstraction/problem solving.
Linear regression analysis adjusting for demographic factors, methamphetamine dependence and HIV serostatus showed that HCV remained a predictor of global impairment (p < 0.02), learning (p < 0.02), abstraction (p < 0.02), and motor skills (p < 0.04).
The ratio of aspartate aminotransferase to alanine aminotransferase -- a surrogate marker of liver dysfunction -- was not related to deficit scores.
"Because hepatitis C is potentially curable, its identification and treatment are likely to result in improved neurobehavioral outcomes among individuals with HIV infection and substance use disorders," Dr. Cherner's group advises.
"Because the majority of HCV-infected adults have additional risk factors for cognitive impairment such as drug or alcohol abuse or HIV infection, the prevalence of cognitive impairment among these persons may be disconcertingly high," Dr. Wilfred G. van Gorp, at Columbia University in New York, and Dr. Charles H. Hinkin, at the David Geffen School of Medicine at UCLA, point out in a related editorial.
Cognitive impairment can significantly affect employment status, medication adherence, and driving safety, so patients with multiple comorbidities should undergo careful assessment of cognitive function, psychiatric symptoms, and daily functioning, they add.
Neurology 2005;64:1328-1329,1343-1347.
AUTHOR DISCUSSION
It is not known whether or how comorbid HCV infection, METH use disorders, and HIV infection may interact to worsen neurobehavioral outcomes. Observations from the current study are consistent with the hypothesis that HCV infection has an independent adverse effect on NP performance and that the effects of HCV, HIV, and METH use are additive. The results are in line with recent studies that describe neurocognitive compromise associated with HCV infection in samples with additional comorbidities. In a sample of polysubstance users, investigators found slower reaction time on a modified Stroop task among HCV+ subjects, relative to HIV+ subjects, with coinfected individuals performing worst.23 Another recent study demonstrated worse performance on a test of abstraction and concept formation among coinfected individuals compared with those with HIV infection alone.24 In two other studies,25,26 NP test performance of chronic HCV patients was compared with that of patients with HCV plus comorbid conditions such as alcoholic hepatitis, HIV, hepatitis B, and other chronic liver diseases. Although deficits in attention and psychomotor speed were observed across all groups, they were most profound among HCV+ patients with comorbid conditions. Patients with chronic HCV without comorbid conditions were comparable with those with other chronic liver disease. Although a correlation was found between cognitive dysfunction and degree of hepatic fibrosis, noncirrhotic subjects had similar levels of cognitive impairment as cirrhotic subjects in many domains, suggesting that chronic liver disease, even without cirrhosis, is associated with cognitive deficits. Patients with chronic HCV were found to be impaired on more cognitive tasks than a group that had cleared HCV.17 Impairments were seen in concentration and working memory that were independent of depression, fatigue, history of injection drug use, or symptom severity.
No consensus exists regarding HCV neuropathogenesis, but some theories have been postulated.17,27,28 First, HCV may injure the brain by replicating in resident or trafficking cells. In support of this, investigators have identified that HCV can replicate in the CNS, probably in cells of macrophage lineage.29–31 Similar to HIV, HCV might use monocyte-derived cells to enter the brain, where it could then infect resident cells. Second, infected or activated cells in the CNS may release inflammatory mediators, which can attract additional immune cells into the CNS32 and injure neural cells. This theory is supported by the association of HCV infection with production of tumor necrosis factor- {alpha} in CSF22 and with higher choline/creatine ratios and decreased N-acetylaspartate levels on MR spectroscopy.27,33 Third, in HCV/HIV-coinfected individuals, HCV may up-regulate HIV replication in trafficking macrophages. This theory is supported by the association between HCV infection and higher HIV RNA levels in CSF.22 Other theories of HCV neuropathogenesis are currently under investigation. For example, researchers are exploring whether HCV might injure the brain via neurotoxic HCV-encoded proteins or activation of brain endothelial cells and astrocytes.
HCV-related cognitive impairment might also result from other causes such as excitotoxic injury from hyperammonemia, which often accompanies advanced liver disease. Although we did not directly test ammonia concentrations, levels of common biochemical markers (e.g., transaminases, albumin, platelets) suggest that our study participants did not have sufficiently advanced liver disease to be at risk for hepatic encephalopathy.
Additionally, although we modeled lifetime diagnosis of alcohol dependence statistically (recent or chronic alcoholism was an exclusion criterion), the substantial prevalence of this disorder among HCV+ subjects warrants a more detailed analysis of the influence of alcohol exposure on NP functioning in this population with comorbid risks for liver dysfunction. Given its scope, this exploration is left for a separate manuscript. A preliminary analysis, however, showed that cumulative lifetime exposure to alcohol was greater in HCV+ individuals but was not correlated significantly with NP performance.
The current study adds to evidence that HCV infection has implications for brain functioning, even in the absence of advanced liver disease, and represents an early attempt at exploring the neurobehavioral consequences of possible synergy between comorbid risk factors. However, the study is limited by the lack of an HCV-monoinfected group unconfounded by METH dependence. As the original data collection was not designed to account for HCV, the available study groups were unbalanced, making it difficult to detect individual effects on brain functioning. To distinguish whether any one factor, or a specific combination, accounts for differences in the pattern or degree of NP deficits, a balanced, factorial study that includes sufficient subjects with each factor alone and in combination is required. The statistical approach employed in the current analyses is, by necessity, an imperfect attempt to tackle this question. Nevertheless, it can be argued that the participants in this study are largely representative of individuals with HCV infection, as evidenced by the degree of confounding factors reported in the extant literature and given the viral mode of transmission.
Future research directions might consider the relationship of plasma HCV burden and fibrosis indicators to NP impairment as well as effects of HCV treatment on cognitive performance. It will also be important to determine whether HCV and/or METH facilitate HIV penetration into the CNS, affect rate of neurocognitive decline, or alter neurologic response to HIV treatment. Multidisciplinary research that includes diverse sources of information (e.g., behavioral, imaging, neurobiology, and neuropathology), with proper representation of risk factors, would compose the ideal system in which to tackle the complexities of potential synergy in biologic mechanisms that may account for the increased vulnerability to neurocognitive dysfunction observed in these multirisk populations. Because hepatitis C is potentially curable, its identification and treatment are likely to result in improved neurobehavioral outcomes among individuals with HIV infection and substance use disorders.
Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine
M. Cherner, PhD, S. Letendre, MD, R. K. Heaton, PhD, J. Durelle, BS, J. Marquie-Beck, BA, B. Gragg, BS, I. Grant, MD and the HIV Neurobehavioral Research Center Group
From the Departments of Psychiatry (Drs. Cherner, Heaton, and Grant) and Medicine (Dr. Letendre, J. Durelle, J. Marquie-Beck, and B. Gragg), University of California San Diego, and VA San Diego Healthcare System (Dr. Grant), CA.
ABSTRACT
Objective: To examine the contribution of hepatitis C virus (HCV) infection to neurocognitive dysfunction in individuals with comorbid HIV infection or methamphetamine (METH) dependence.
Methods: Neurocognitive functioning was examined in 430 study participants who were either normal controls or had HCV infection, HIV infection, history of METH dependence, or combinations of these factors as risks for cognitive deficits.
Results: Rates of global and domain-specific neuropsychological (NP) impairment increased with the number of risk factors. HCV serostatus was a significant predictor of NP performance both globally and in the areas of learning, abstraction, and motor skills, with trends in speeded information processing and delayed recall. HCV serostatus did not predict scores in attention/working memory or verbal fluency.
Conclusion: Hepatitis C virus infection contributes to the neuropsychological deficits observed among HIV-infected and stimulant-dependent populations.
FULL TEXT OF STUDY FOLLOWS COMMENTARY BELOW
COMMENTARY
Triple trouble
Cognitive deficits from hepatitis C, HIV, and methamphetamine
Wilfred G. van Gorp, PhD and Charles H. Hinkin, PhD
From Columbia University (Dr. van Gorp), College of Physicians & Surgeons, Department of Psychiatry, New York, NY; and Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, and VA Greater Los Angeles Health Care System (Dr. Hinkin), Los Angeles, CA.
In this issue of Neurology, Cherner et al.1 discuss both the negative impact of hepatitis C (HCV) infection upon cognitive functioning and, equally importantly, the additive effect of methamphetamine abuse, HIV infection, and HCV infection upon cognition. Not only does each appear to represent an independent risk factor for neuropsychological impairment, but when they are combined in the same individual, the risk for more severe neuropsychological impairment is greatly increased. Cherner et al. also demonstrate that these effects are not only seen at a global cognitive level, but also differentially target specific neuropsychological domains.
Before commenting on the importance of this research, several methodologic concerns bear mention. First, the prevalence of substantial alcohol use was high in their sample. The noninfected participants drank an average of 3.3 alcoholic drinks per day, while the highest risk group had an average lifetime alcohol consumption of over six alcoholic drinks per day, with the consumption of alcohol increasing as the number of risk factors increased. Also, as this study was not initially undertaken specifically to study the effects of HCV infection, some subject groupings in the study had fewer participants than would be optimal. For instance, of the 430 subjects in the sample, only 83 were HCV infected. Only 2 subjects were solely HCV infected and neither HIV positive or methamphetamine dependent, hence limiting conclusions that can be drawn regarding the specific neurocognitive effects of HCV. While the authors used statistical methods to control for and examine these effects, different methods are needed: a sufficient number of participants per cell and equivalent alcohol consumption by group. The authors note that a prospective study is needed.
These limitations notwithstanding, this study draws attention to a burgeoning public health crisis with great relevance to neurology. Approximately 2.7 million Americans are infected with HCV, many of whom will develop hepatic disease as well as neurologic dysfunction. In the United States, HCV mortality rates exceed HIV infection. While HIV and HCV share common risk factors and routes of transmission, this study and others suggest that both viruses result in similar neurocognitive and neuropsychiatric consequences.1–3 Studies using 1H-MRS have found similar metabolic abnormalities in HIV and HCV infection such as increased choline/creatine ratios in frontostriatal regions.4,5 HCV replicates in the same cells as HIV (monocytes/macrophages and T and B lymphocytes) and there is evidence that HIV infection may facilitate HCV replication.6 Thus, there is reason to conclude that HIV/HCV coinfection may have an additive, if not synergistic, effect. Substance abuse present in the majority of HCV+ adults can be expected to magnify deficits.
It is evident that HCV may cause major cognitive impairment among those infected. However, because the majority of HCV-infected adults have additional risk factors for cognitive impairment such as drug or alcohol abuse or HIV infection, the prevalence of cognitive impairment among these persons may be disconcertingly high. Research with similar populations has shown that even mild levels of neuropsychological impairment can have significant effects on key domains such as employment status,7,8 medication adherence,9 and driving safety.10 For this reason, the Cherner et al. study merits careful attention and scrutiny. In these patients with multiple comorbid risk factors, careful assessment of cognitive function and psychiatric symptoms—especially drug and alcohol use and ability to carry out higher order activities—should be assessed. Finally, because self-report of cognitive functioning does not correlate well with actual performance on cognitive tests, mental status testing and assessment of daily functioning (ideally by informants) is essential.
The Cherner et al. study investigated only three risk factors (HCV infection, HIV infection, and methamphetamine abuse) that could increase the frequency of cognitive impairment in this population. Other factors could be additive with HCV infection to produce even greater cognitive impairment: head injury, learning disability, or psychiatric disease. All these risk factors merit evaluation in this population.
References
1. Cherner M, Letendre S, Heaton RK, et al. Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine. Neurology 2005;63:1343–1347.
2. Hilsabeck RC, Castellon SA, Hinkin CH. Neuropsychological aspects of co-infection with human immunodeficiency virus and hepatitis C virus (HIV/HCV). Clin Infect Dis 2005 (in press).
3. Hilsabeck RC, Hassanein TI, Carlson MD, Ziegler EA, Perry W. Cognitive functioning and psychiatric symptomatology in patients with chronic hepatitis C. J Int Neuropsychol Soc 2003;9:847–854.
4. Chang L, Ernst T, Leonido-Yee M, Walot I, Singer E. Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex. Neurology 1999;52:100–108.
5. Forton DM, Allsop JM, Main J, Foster GR, Thomas HC, Taylor-Robinson SD. Evidence for a cerebral effect of the hepatitis C virus. Lancet 2001;58:38–39.
6. Laskus T, Radkowski M, Jablonska J, et al. Human immunodeficiency virus facilitates infection/replication of hepatitis C virus in native human macrophages. Blood 2004;103:3854–3859.
7. van Gorp W, Baerwald JP, Ferrando SJ, McElhiney MC, Rabkin JG. The relationship between employment and neuropsychological impairment in HIV infection. J Int Neuropsychol Soc 1999;5:534–539.
8. Heaton RK, Marcotte TD, Mindt M, et al. The impact of HIV-associated neurological impairment on everyday functioning. J Int Neuropsychol Soc 2004;10:317–331.
9. Hinkin CH, Castellon SA, Durvasula RS, et al. Medication adherence among HIV+ adults: effects of cognitive dysfunction & regimen complexity. Neurology 2002;59:1944–1950.
10. Marcotte TD, Heaton RK, Wolfson T, et al. The impact of HIV-related neuropsychological dysfunction on driving behavior. J Int Neuropsychol Soc 1999;5:579–592.
FULL TEXT
Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine
M. Cherner, PhD, S. Letendre, MD, R. K. Heaton, PhD, J. Durelle, BS, J. Marquie-Beck, BA, B. Gragg, BS, I. Grant, MD and the HIV Neurobehavioral Research Center Group
From the Departments of Psychiatry (Drs. Cherner, Heaton, and Grant) and Medicine (Dr. Letendre, J. Durelle, J. Marquie-Beck, and B. Gragg), University of California San Diego, and VA San Diego Healthcare System (Dr. Grant), CA.
INTRODUCTION
HIV infection can be accompanied by neurocognitive impairment consistent with frontostriatal dysfunction.1–5 Lifestyle factors such as needle sharing and sexual contact with multiple partners have led to a relatively high prevalence of HIV infection among methamphetamine (METH) users.6,7 Chronic or heavy exposure to METH, without comorbid HIV infection, has also been associated with neuropsychological (NP) abnormalities.8–13 A substantial proportion of METH users, both with and without HIV infection, may also be infected with hepatitis C virus (HCV).14–16
There is evidence that HCV is neurotropic and may cause NP impairment even in the absence of advanced liver disease.17 Thus, it is possible that neurocognitive dysfunction observed in individuals with HIV infection or substantial METH use may in part be a consequence of, or be augmented by, previously undetected concomitant HCV infection. In the current study, we investigated the contribution of HCV infection to the prevalence of global and domain-specific NP impairment in a convenience sample of participants with different combinations of HIV infection, METH dependence, and HCV infection as risk factors for neurocognitive deficits. We hypothesized that the prevalence of impairment would increase with the number of risk factors and that HCV seropositivity would contribute to cognitive impairment above and beyond the role of HIV serostatus and METH dependence.
RESULTS
Prevalence of HCV infection in cohort. Because the original purpose of the parent program project concerned effects of HIV and METH, participants were not recruited with the intention to represent HCV-infected individuals. However, substantial numbers of HCV+ participants were discovered retrospectively, particularly among the METH+ groups. The prevalence of HCV infection was 37% among HIV+ METH+ participants, 28% among METH+ only, 7% among HIV+ only, and 2% among HIV– METH– subjects. The table summarizes demographic and clinical characteristics of the study participants, stratified by HCV serostatus. HCV+ subjects were slightly older, had somewhat lower level of education, were more likely to have been diagnosed with episodic alcohol dependence in the past, and had elevated indicators of liver function. 83 subjects were HCV+, 347 subjects HCV-negative.
The resulting composition of the 430 participants was as follows: HCV– HIV– METH– = 90, HCV– HIV– METH+ = 83, HCV– HIV+ METH– = 105, HCV+ HIV– METH– = 2, HCV– HIV+ METH+ = 69, HCV+ HIV– METH+ = 33, HCV+ HIV+ METH– = 8, HCV+ HIV+ METH+ = 40. In terms of number of risk factors, this corresponds to 90 participants with none (i.e., normal controls), 190 subjects with one risk (HIV, or METH, or HCV), 110 with two, and 40 with all three risk factors.
Prevalence of NP impairment. With use of the number of risk factors as a grouping variable, a {chi}2 test was employed to determine the significance of group differences in the proportion of global NP impairment (as determined by obtaining a global deficit score of ≥0.5). The prevalence of global NP impairment increased with the number of risk factors (overall {chi}2 = 23.86, p < 0.0001). Analysis of the individual ability domains showed a similar pattern, with differences in the proportion of impairment according to increasing number of risk factors in the areas of learning, motor speed and dexterity, delayed recall, and abstraction/problem solving, with a trend in speeded information processing. The proportion of impairment in attention/working memory was greater among the risk groups than in control subjects but did not increase linearly with the number of risk factors (figure).
Contribution of HCV serostatus to NP impairment. To determine whether HCV infection affected NP impairment above and beyond the contribution of HIV infection and METH dependence, we performed linear regressions predicting global and domain deficit scores. After adjusting for age, education, gender, race (white/nonwhite), history of alcohol dependence diagnosis, history of METH dependence diagnosis, and HIV serostatus, we found that HCV serostatus was a predictor of global impairment (p < 0.02) as well cognitive functioning in the areas of learning (p < 0.02), abstraction (p < 0.02), and motor skills (p < 0.04), with trends in speeded information processing (p < 0.06) and delayed recall (p < 0.09). HIV serostatus remained a predictor of the global (p < 0.004), learning (p < 0.02), delayed recall (p < 0.03), abstraction (p < 0.01), and speeded information processing (p < 0.03) deficit scores, with trends in attention/working memory (p < 0.07) and motor ability (p < 0.08). METH dependence remained a predictor of global (p < 0.02), learning (p < 0.002), delayed recall (p < 0.03), attention/working memory (p < 0.02), and motor (p < 0.005) performance, with a trend in abstraction (p < 0.07).
Alcohol exposure also increased with the number of risk factors, such that the average lifetime number of drinks consumed per day of use were 3.3 (SD 2.9) for control subjects, 5.1 (4.4) for those with one risk factor, 6.6 (5.2) for those with two risk factors, and 6.4 (4.9) for the three-risk group (p < 0.0001). When the average daily quantity was used in the regressions instead of lifetime diagnosis of alcohol dependence, the results remained essentially unaltered.
As we did not obtain liver biopsy information to determine hepatic fibrosis stage, we used available transaminase data in the form of the ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) as a surrogate21 to determine the influence of liver dysfunction on NP performance among the HCV+ subjects. In correlative analyses, we found no significant relationship of the AST/ALT ratio with any of the deficit scores. Relationships between HCV viral burden and NP functioning along with other HCV-related biomarker abnormalities are reported elsewhere.22
METHODS
Subjects. Subjects were 430 men and women participating in the program project on NeuroAIDS Effects of Methamphetamine at the University of California San Diego. They were recruited from substance dependence recovery programs and from the San Diego community. HIV infection was diagnosed by standard clinical antibody detection upon entry into the study. HCV serostatus was determined retrospectively by standard clinical antibody detection, and degree of liver disease was indexed by level of hepatic transaminases with clinical assays performed by standard methods. HCV+ participants were not undergoing interferon or combination interferon/ribavirin treatment at the time of their study visit. Urine testing for common recreational drugs was performed at the time of the study visit using the Rapid Drug Screen (Phamatic Inc., San Diego, CA). Lifetime history of substance use disorders, including meth dependence (METH+), was ascertained using the Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders (4th ed.).18 METH+ participants were required to meet lifetime dependence criteria, with abuse in the last 18 months.
Potential participants were excluded if they met criteria for a lifetime diagnosis of dependence on any other substance, excepting cannabis or alcohol because of their very high prevalence among the METH+ population. However, subjects with chronic long-term alcoholism or alcohol dependence within the last 12 months were excluded. Participants were requested to be abstinent from METH for at least 10 days prior to testing and show negative urine toxicology on the day of the assessment. In addition, subjects were excluded if they had neurologic or metabolic conditions unrelated to the risk factors of interest that might confound the interpretation of findings (e.g., psychosis, traumatic brain injury with loss of consciousness for >30 minutes). The normal control group consisted of participants who never met criteria for abuse or dependence for METH or other amphetamines and who were not regular stimulant users, in addition to meeting the general inclusion/exclusion criteria. All subjects provided written informed consent prior to participation.
Measures. Determination of impairment. Study participants underwent a comprehensive NP battery to assess functioning in the areas of learning, recall, attention/working memory, speeded information processing, verbal fluency, abstraction/problem solving, and motor ability. The Appendix lists the tests used to assess each domain of cognitive functioning. Individual test scores were standardized and combined to create global and domain-specific deficit scores in the following fashion: Raw test scores were converted to T scores (standard scores with a mean of 50 and SD of 10) using demographically corrected norms to account for the effects of age, education, gender, and ethnicity, as appropriate and available for each measure. A 0- to 5-point deficit rating was then assigned to the demographically corrected T scores for each test, as follows: T > 39 = 0 (no impairment), T 35 to 39 = 1 deficit point; T 30 to 34 = 2 points; T 25 to 29 = 3 points; T 20 to 24 = 4 points; T < 20 = 5 points. The global and domain-specific deficit scores were computed by adding the deficit points of the component test measures and dividing by the number of measures in a domain or over the whole battery for the global deficit score.
The resulting deficit scores are objective summary scores that reflect the number and severity of impaired performances throughout the test battery and give relatively less weight to test performances that are within normal limits. The deficit scores were used to classify individual subjects with respect to presence or absence of NP impairment. Global and domain deficit scores of ≥0.50 are considered impaired.19,20 This cutoff reflects an average of at least mild impairment on at least half of the component measures.
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