Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Int Neuropsychol Soc. Author manuscript; available in PMC 2014 May 23.
Published in final edited form as:
PMCID: PMC4031745

Neurocognitive Effects of HIV, Hepatitis C, and Substance Use History


HIV-associated neurocognitive dysfunction persists in the highly active antiretroviral therapy (HAART) era and may be exacerbated by comorbidities, including substance use and hepatitis C virus (HCV) infection. However, the neurocognitive impact of HIV, HCV, and substance use in the HAART era is still not well understood. In the current study, 115 HIV-infected and 72 HIV-seronegative individuals with significant rates of lifetime substance dependence and HCV infection received comprehensive neuropsychological assessment. We examined the effects of HIV serostatus, HCV infection, and substance use history on neurocognitive functioning. We also examined relationships between HIV disease measures (current and nadir CD4, HIV RNA, duration of infection) and cognitive functioning. Approximately half of HIV-infected participants exhibited neurocognitive impairment. Detectable HIV RNA but not HIV serostatus was significantly associated with cognitive functioning. HCV was among the factors most consistently associated with poorer neurocognitive performance across domains, while substance use was less strongly associated with cognitive performance. The results suggest that neurocognitive impairment continues to occur in HIV-infected individuals in association with poor virologic control and comorbid conditions, particularly HCV coinfection.

Keywords: Neuropsychology, HIV-1, Chronic hepatitis C, Viral load, Cocaine dependence, Opiate dependence


Despite a dramatic decrease in the incidence of severe neurocognitive and functional impairment in HIV-infected people since the availability of highly active antiretroviral therapy (HAART), milder forms of HIV-associated neurocognitive disorders (HAND) remain commonly observed (McArthur, 2004). Recent studies in the HAART era suggest the continued occurrence of HAND in as many as half of HIV-infected individuals (Heaton et al., 2010; Tozzi et al., 2007; Woods, Moore, Weber, & Grant, 2009). These disorders are characterized by impairments in psychomotor functioning, information processing speed, attention, executive functioning, and working memory (Brew, 2004; Heaton et al., 1995; Sacktor et al., 2002) and have been linked to frontal-subcortical brain disturbances, including cerebral metabolite abnormalities (Cohen, Harezlak, Gongvatana, et al., 2010; Paul et al., 2007, 2008) and white matter damage (Chen et al., 2009; Gongvatana et al., 2009; Pomara, Crandall, Choi, Johnson, & Lim, 2001). Recent findings in HAART-treated cohorts suggest that increasing cortical involvement may also be present (Cohen, Harezlak, Schifitto, et al., 2010; Thompson et al., 2005). Although HAART has been associated with improvements in neurocognitive functioning (Cohen et al., 2001; Cysique et al., 2009; Letendre et al., 2004; Robertson et al., 2004), it is not clear whether these improvements are maintained with long-term treatment, which may be complicated by potential drug resistance and toxicity. Even among patients whose viral load is currently well-controlled, brain dysfunction may exist in association with disease history (e.g., nadir CD4, Cohen, Harezlak, Schifitto, et al., 2010; Robertson et al., 2007).

In addition to the neurocognitive dysfunction attributable to HIV infection itself, comorbid conditions in HIV-infected individuals may significantly affect neurocognitive function in their own right. Because neurocognitive impairments persist despite effective control of HIV by HAART, there has been an increasing focus on these comorbidities as a source of impairment among HIV-infected people. Chiefly, substance use and hepatitis C infection are common comorbidities of HIV that are known to significantly affect brain function (Martin-Thormeyer & Paul, 2009). Substance abuse has been linked to neurocognitive dysfunction and reduced functional outcome both alone and in the context of HIV infection (Basso & Bornstein, 2000; Cherner et al., 2005; Nath, Maragos, Avison, Schmitt, & Berger, 2001; Rippeth et al., 2004). Chronic substance users may exhibit neurocognitive effects similar to those of HIV, including frontal-subcortical damage and impairments in associated functions such as executive functioning, short-term memory, and attention (Ersche, Clark, London, Robbins, & Sahakian, 2006; Fernandez-Serrano, Perez-Garcia, Schmidt Rio-Valle, & Verdejo-Garcia, 2010; Lundqvist, 2005; O’Malley, Adamse, Heaton, & Gawin, 1992). Although the neurocognitive effects of substance use tend to diminish over time following cessation of use (Davis, Liddiard, & McMillan, 2002; Fein, Torres, Price, & Di Sclafani, 2006; van Gorp et al., 1999), chronic heavy substance use can result in long-term cognitive impairments (Di Sclafani, Tolou-Shams, Price, & Fein, 2002; Eldreth, Matochik, Cadet, & Bolla, 2004; Green, Saveanu, & Bornstein, 2004; Pascual-Leone, Dhuna, & Anderson, 1991), which may have important consequences for HIV-infected individuals, even those who have long been abstinent.

Hepatitis C virus (HCV) infection, which affects an estimated 15% to 30% of people living with HIV in the United States (Sherman, Rouster, Chung, & Rajicic, 2002), may also contribute to cognitive impairment in HIV-infected people. There is evidence that chronic HCV infection results in neurocognitive dysfunction, even in the absence of advanced liver disease, with deficits in many of the domains affected by HIV, including attention, executive function, and processing speed (Clifford, Evans, Yang, & Gulick, 2005; Forton et al., 2005, 2002; Hilsabeck, Perry, & Hassanein, 2002; Kramer et al., 2002). There is also emerging evidence suggesting that HIV/HCV coinfection is associated with poorer neurocognitive outcomes than infection with HIV alone (Cherner et al., 2005; Hilsabeck, Castellon, & Hinkin, 2005; Ryan, Morgello, Isaacs, Naseer, & Gerits, 2004).

The neurocognitive impact of HIV infection in the context of comorbid conditions, including HCV and substance use, in the HAART era is still not well understood. Increased understanding of the etiology of neurocognitive impairment in HIV-infected individuals is crucial for the prevention and treatment of brain dysfunction. Consequently, we examined the factors affecting cognitive functioning in a sample of HIV-infected and seronegative individuals with significant rates of HCV infection and lifetime substance use. We hypothesized that individuals with HIV/HCV coinfection and significant substance use history would demonstrate the greatest degree of cognitive impairment. We also hypothesized that greater HIV disease severity (i.e., lower CD4 counts, higher viral load, longer duration of infection) would be associated with poorer cognitive performance.



One hundred eighty-seven participants, consisting of 115 HIV-infected (HIV+) and 72 HIV-seronegative (HIV−) individuals, were enrolled in the study. Participants were recruited from The Miriam Hospital Immunology Center as part of an NIH-sponsored study of HIV-associated brain dysfunction. The study was approved by the institutional review boards, and informed consent was obtained from each participant before enrollment. All participants underwent a neurological examination and thorough medical history assessment. HIV infection was documented by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blot. Active HCV infection was defined as positive anti-HCV by ELISA and positive qualitative HCV RNA by polymerase chain reaction. Participants were excluded for history of (1) head injury with loss of consciousness >10 minutes; (2) history of neurological conditions including dementia, seizure disorder, stroke, and opportunistic infection of the brain; (3) severe psychiatric illness that might impact brain function, for example, schizophrenia; and (4) current (6-month) substance dependence or positive urine toxicology screen for cocaine, opiates, or illicit stimulants or sedatives.

Demographic and clinical characteristics of the participant population are presented in Table 1. Mean duration of HIV infection was 12.6 years, and the majority (82.6%) of the HIV+ group was on stable HAART. Most HIV+ participants (70.5%) had undetectable plasma HIV RNA (<75 copies/mL). Despite an average nadir CD4 of 181 cells/µL, indicating a history of immunocompromise, participants were medically stable, with an average current CD4 count of 461 cells/µL. Fifty-one participants, including 42 HIV+ (36.5%) and 9 HIV− (12.5%) participants, had active HCV infection. HCV infection was significantly more common in the HIV+ group (χ2[1,N = 187] = 12.88; p < .001). No participants were receiving interferon or ribavirin at the time of testing.

Table 1
Characteristics of HIV+ and HIV− participants

The Kreek-McHugh-Schluger-Kellogg Scale (KMSK scale, Kellogg et al., 2003) was used to assess lifetime alcohol and substance dependence. Using this classification system, respective rates of alcohol, cocaine, and opiate dependence were 49.6%, 54.8%, and 16.5% in the HIV+ group and 44.4%, 26.4%, and 6.9% in the HIV− group. Depression was assessed using the Center for Epidemiologic Studies Depression (CES-D) scale (Radloff, 1977). Mean CES-D scores for the HIV+ and HIV− groups were 21.5 and 14.4, respectively.

HIV+ participants had significantly fewer years of education (F[1,186] = 4.70; p = .031), higher rates of cocaine dependence (χ2[1,N = 187] = 14.50; p < .001), and higher degree of depression (F[1,182] = 14.04; p < .001). HCV-infected participants of either HIV status were more likely to be nonwhite (χ2[4,N = 187] = 10.28; p = .036) and had fewer years of education (F[1,186] = 13.90; p < .001) and higher rates of cocaine (χ2[1,N = 187] = 38.03; p < .001) and opiate (χ2[1,N = 187] = 37.38; p < .001) dependence. HIV/HCV-coinfected participants had longer duration of HIV infection (F[1,114] = 14.98; p < .001) than HIV-monoinfected participants.

Neurocognitive Assessment

Neurocognitive functioning was assessed in the following domains: speed of information processing, attention/working memory/executive functioning, learning, memory, verbal fluency, and psychomotor speed. The battery was comprised of the following tests chosen for their sensitivity to HAND: Hopkins Verbal Learning Test – Revised (HVLT-R; Benedict, Schretlen, Groninger, & Brandt, 1998; Brandt & Benedict, 1991); Brief Visuospatial Memory Test – Revised (BVMT-R; Benedict, 1997); Controlled Oral Word Association Test (COWAT–FAS; Benton, Hamsher, & Sivan, 1994); category fluency (animals); Stroop Color and Word Test (Golden, 1978); Trail Making Test, Parts A and B (Reitan, 1992); Grooved Pegboard Test (Kløve, 1963); and the Digit Symbol–Coding, Symbol Search, and Letter-Number Sequencing tests from the Wechsler Adult Intelligence Scale – Third Edition (WAIS-III; Wechsler, 1997). Tests, grouped by domain, are listed in Tables 3 and and4.4. The present tests and domains are similar to those used in the Global Deficit Score (GDS), which has shown high validity in detecting HIV-associated neurocognitive impairment (Carey et al., 2004; Heaton et al., 1995).

Table 3
Regression coefficients (β) for neurocognitive performance in the whole group as a function of HIV serostatus, HCV, and substance use history
Table 4
Regression coefficients (β) for neurocognitive performance in the HIV+ group as a function of HIV clinical measures, HCV, and substance use history

Demographically corrected t scores were calculated using established norms (Benedict et al., 1998; Benedict, Schretlen, Groninger, Dobraski, & Shpritz, 1996; Heaton, Miller, Taylor, & Grant, 2004). Domain composite scores were calculated by averaging the t scores of all tests in the domain. Overall composite scores were calculated by averaging the t scores of all tests in the battery. Means and standard deviations of domain and overall scores, grouped by HIV and HCV status, are presented in Table 2.

Table 2
Neurocognitive performance by HIV and HCV status

Statistical Analysis

Statistical analysis was performed using SPSS software (IBM). Group differences in demographic, substance use, and clinical variables were assessed using analysis of variance or Pearson’s χ2. All participants with a history of opiate dependence also had a history of cocaine dependence; consequently, cocaine and opiate histories were combined into one binary variable indicating history of either drug. Multiple linear regression analyses were performed with each cognitive test and composite score as the dependent variable. Two primary sets of analyses were performed. (1) The first set of analyses included all participants. HIV status, HCV status, lifetime alcohol dependence, and lifetime cocaine or opiate dependence served as predictors. The same analyses were performed with CES-D as an additional predictor. (2) The second set of analyses included HIV+ participants only. Current CD4 count, nadir CD4 count, HIV RNA level, duration of HIV infection, HCV status, lifetime alcohol dependence, and lifetime cocaine or opiate dependence were entered as predictors.


Contributors to Neurocognitive Performance in the Whole Cohort

Neurocognitive performance in the whole cohort was assessed as a function of HIV serostatus, HCV infection, lifetime alcohol dependence, and lifetime cocaine/opiate dependence. Results are presented in Table 3. HCV infection was significantly associated with poorer performance on Digit Symbol–Coding (p < .001), Symbol Search (p = .004), BVMT total recall (p = .004), and BVMT delayed recall (p = .008), and composite scores for processing speed (p = .013), learning (p = .030), memory (p = .007), and overall performance (p = .014). Cocaine/opiate dependence was significantly associated with poorer BVMT delayed recall (p = .040). HIV serostatus and alcohol history were not significantly associated with neurocognitive performance.

To examine the contribution of depressive symptoms to neurocognitive performance, CES-D score was added as an additional predictor in the regression model described above. Higher degree of depression was associated with poorer processing speed (p < .001), attention/executive functioning (p = .010), motor functioning (p = .001), and overall performance (p < .001). Follow-up analyses showed significant associations between CES-D and overall performance in both the HIV− group (p = .014) and the HIV+ group (p = .004). The effects of HCV on neurocognitive performance remained regardless of whether CES-D was included in the model. When CES-D was included, substance use was no longer associated with poorer performance.

Contributors to Neurocognitive Performance in the HIV+ Group

In secondary analyses of the HIV+ group alone, neurocognitive performance was assessed as a function of HIV disease measures, HCV infection, and substance use. Results are presented in Table 4. HCV infection was significantly associated with poorer performance on Digit Symbol–Coding (p = .007), Symbol Search (p = .001), BVMT total recall (p = .002), HVLT delayed recall (p = .038), and BVMT delayed recall (p = .007), and composite scores for processing speed (p = .008), learning (p = .007), memory (p = .003), and overall performance (p = .006). Detectable HIV RNA was significantly associated with poorer performance on Trail Making Test Part B (p = .039), HVLT delayed recall (p = .019), FAS Letter Fluency (p = .002), and composite scores for verbal fluency (p = .016) and overall performance (p = .016). Duration of HIV infection was significantly associated with Trail Making Test Part B (p = .014) and the attention/working memory/executive functioning domain score (p = .026). Surprisingly, longer duration of infection was associated with better performance on these measures. Current and nadir CD4 and history of substance dependence were not significantly associated with any cognitive measure in the HIV+ cohort.


In this cohort of 115 HIV-infected (HIV+) and 72 seronegative (HIV−) individuals, we found significant associations between neurocognitive deficits and HIV viral load, hepatitis C virus (HCV) coinfection, and substance use history. HIV RNA and HCV coinfection were significant predictors of overall neurocognitive performance. Detectable HIV RNA was also associated with reduced executive functioning, verbal fluency, and memory, and HCV coinfection was associated with reduced processing speed, learning, and memory. Substance use was associated with reduced visuospatial memory. Depression also contributed to neurocognitive impairment in addition to the other clinical variables examined. Consistent with a recent report in a large national cohort (Heaton et al., 2010), approximately half of our HIV+ cohort exhibited significant neurocognitive impairment (Carey et al., 2004). The findings from this cohort of medically stable HIV-infected individuals support the persistence of neurocognitive dysfunction in the HAART era (Clifford, 2008; Harezlak et al., 2011; Robertson et al., 2007; Tozzi et al., 2007), particularly in association with active HIV infection and HCV coinfection.

Detectable plasma HIV RNA level was a strong determinant of cognitive impairment, which emphasizes the importance of effective systemic virologic control in mitigating brain dysfunction. However, it is also possible that preexisting neurocognitive impairment contributes to poor treatment adherence and other health behaviors which may result in loss of virologic control. In contrast with viral load, other disease severity measures examined, including current and nadir CD4, were not significantly associated with impairment. The absence of significant associations between nadir CD4 and cognitive performance was somewhat unexpected given emerging evidence indicating an association between past immunocompromise and current neurocognitive function (Cohen, Harezlak, Schifitto, et al., 2010; Tozzi et al., 2005; Valcour et al., 2006); however, it has been suggested that effects of HIV disease markers may be difficult to examine in the context of comorbid conditions that may affect neurocognitive functioning (Heaton et al., 2010). The relationship between longer duration of infection and better performance was surprising since we might expect neurocognitive functioning to worsen over the course of HIV infection in association with progressive neurodegeneration (Bornstein, Nasrallah, Para, Whitacre, & Fass, 1994; Brew, Crowe, Landay, Cysique, & Guillemin, 2009; Harezlak et al., 2011; Valcour, Shikuma, Watters, & Sacktor, 2004). Instead, the results suggest that the relationship between duration of infection and brain dysfunction may not be straightforward (Cysique, Maruff, & Brew, 2006; Ellis, Langford, & Masliah, 2007; Moore et al., 2006; Robertson et al., 2004; Tozzi et al., 2007) and should be examined in future studies. In sum, while the relationships between HIV clinical variables and neurocognitive impairment appear to be complex, the present findings indicate a continued relationship between HIV and neurocognitive functioning, particularly in association with active infection.

In analyses in the whole cohort of HIV-infected and seronegative individuals, the absence of an association between HIV serostatus and neurocognitive performance was noteworthy. However, it is perhaps unsurprising given the stable medical status of this mostly HAART-treated HIV+ cohort. HIV-associated neurocognitive dysfunction is less commonly observed among individuals with intact immune function and viral suppression (Chang et al., 2002; Childs et al., 1999; Janssen et al., 1989; McArthur et al., 1997; McCutchan et al., 2007), which is emphasized by our HIV RNA finding. Additionally, several studies have observed structural brain changes only among individuals with advanced HIV disease (Gongvatana et al., 2009; Hesselink, Tien, Spoto, Jernigan, & Grant, 1991; Jernigan et al., 1993). Therefore, HIV serostatus may have limited utility as a predictor of neurocognitive impairment in the context of effective virologic and immunologic control (Stern et al., 1998), and measures of disease severity may be more useful in this regard. In the present sample, although 52% of HIV+ participants exhibited neurocognitive impairment in comparison with 35% of the HIV− group, serostatus failed to significantly predict this difference.

The relatively high rate of neurocognitive impairment (35%) in the HIV-seronegative group may appear surprising. However, this may not be entirely unexpected considering that we directed recruitment efforts toward a seronegative comparison sample closely resembling the HIV-infected cohort, with the goal of minimizing potential confounding effects of demographics and other variables. Consequently, rates of comorbid factors, including HCV infection, substance use, and depression, were considerably higher in the HIV− group than in the general population (Compton, Thomas, Stinson,& Grant, 2007; Grant, 1996; Hasin, Stinson, Ogburn,& Grant, 2007; Kim, 2002; Radloff, 1977). In particular, 13% of the HIV-seronegative group had active HCV infection, in comparison with 1.6% of the United States population (Armstrong et al., 2006), and 26% had lifetime non-alcohol substance dependence, in contrast with 2.6% of the general population (Hasin et al., 2007). We found each of these factors to be significantly associated with neurocognitive impairment in the present cohort, indicating their contribution to cognitive dysfunction in the HIV-group as well as in the HIV+ group. In sum, the absence of significant associations between serostatus and neurocognitive functioning may be due to the nature of our HIV− cohort, which more naturalistically emulates HIV-infected people and thus should serve as a valid comparison sample for examining the effects of clinical factors on neurocognitive function.

The apparent effects of HCV coinfection on neurocognitive function in this cohort were particularly striking. HCV was among the strongest determinants of neurocognitive dysfunction in the sample, particularly in the domains of processing speed, learning, memory, and overall performance. These effects remained significant even after controlling for depression and substance use history. Our findings add to mounting evidence that HCV coinfection is associated with neurocognitive dysfunction in HIV-infected individuals (Cherner et al., 2005; Clifford et al., 2005; Hinkin, Castellon, Levine, Barclay, & Singer, 2008; Morgello et al., 2005). Results from our group from the same cohort indicate that HCV coinfection is also among the strongest predictors of white matter integrity (Gongvatana et al., 2011) and plasma inflammatory cytokine levels (Cohen et al., 2011).

The robust effects of HCV may be partly explained by the current state of HCV management in HIV-infected people. Whereas HIV is often effectively controlled by modern antiretroviral treatment, as it was in the present cohort, treatment of HCV is less frequently initiated, completed, and successful in HIV/HCV-coinfected individuals (Carrat et al., 2004; Chung et al., 2004). While HIV-related morbidity and mortality have declined (Crum et al., 2006; Mocroft et al., 2003), HCV-related liver disease has emerged as a leading cause of morbidity and mortality among HIV-infected individuals (Bica et al., 2001; Monga et al., 2001; Palella et al., 2006; Weber et al., 2006). The present findings suggest that HCV infection poses a similar threat to neurocognitive functioning in the HAART era.

The relative contributions of HCV itself and resultant liver disease to brain dysfunction remain to be determined. Our HCV findings were observed in a sample with minimal prevalence of advanced liver disease, suggesting possible direct effects of the virus itself (Forton et al., 2001; Perry, Hilsabeck, & Hassanein, 2008; Weissenborn et al., 2004). Evidence suggesting penetration of the central nervous system by HCV has been observed (Laskus et al., 2002; Letendre et al., 2007; Wilkinson, Radkowski, & Laskus, 2009), although direct links between neurocognitive functioning and HCV RNA have not been established (Clifford et al., 2009). Considering the links between liver disease and neurocognitive dysfunction (Bajaj, Wade, & Sanyal, 2009; de la Monte, Longato, Tong, DeNucci, & Wands, 2009; de la Monte et al., 2010; McCrea, Cordoba, Vessey, Blei, & Randolph, 1996; Tarter et al., 1984), future research should account for markers of liver disease, including liver function tests and fibrosis stage, as well as quantitative HCV RNA to examine the relative contributions of the virus and secondary liver dysfunction to neurocognitive impairment. Additionally, it will be important to examine whether the neurocognitive effects of HCV infection are augmented by coinfection with HIV. Such analysis was not possible in the current study due to the breakdown of HIV/HCV sample sizes, which, while adequate for examining the main effects of each condition, prevents a valid examination of their statistical interaction. Future studies should include balanced HIV/HCV sample sizes to examine this interaction. However, whether the observed HCV associations are due to direct effects of HCV, secondary liver dysfunction, or interaction with HIV, the present findings suggest that successful treatment of HCV may result in improved neurocognitive outcomes for HIV/HCV-coinfected individuals.

The potential contribution of substance use to the present HCV findings also deserves mention. Substance use, especially of intravenous drugs, is among the most significant risk factors for HCV infection; this is reflected in the strong association between HCV and lifetime substance dependence in our sample. Thus, it is nearly impossible to completely disentangle the individual contributions of HCV and substance use to neurocognitive impairment. Nonetheless, regardless of the etiology, the results suggest that HCV coinfection presents increased risk for neurocognitive dysfunction in HIV-infected people, which has both research and clinical implications. The present findings underline the importance of considering this significant comorbid condition in the study and diagnosis of neurocognitive disorders in HIV-infected individuals.

A relatively weak association between lifetime substance use history and cognitive performance was found, which supports the idea that long-term neurocognitive effects of substance use diminish with prolonged abstinence (Davis et al., 2002; Fein et al., 2006; Pezawas et al., 1998). Current substance use, which was excluded from the current study, may be expected to have a greater impact on neurocognitive functioning than remote use. Additionally, examination of the degree of substance use (e.g., lifetime exposure, addiction severity, and length of abstinence) as opposed to the binary diagnosis used here may be more useful for studying the impact of substance use history in the context of HIV infection.

We did observe one significant association between substance use history and neurocognitive impairment in the present sample. Lifetime cocaine or opiate dependence was associated with poorer visuospatial memory, which supports previous similar findings (Fals-Stewart, Schafer, Lucente, Rustine, & Brown, 1994; Gruber, Silveri, & Yurgelun-Todd, 2007), although it is unclear whether the present finding is attributable to cocaine, opiates, or both substances. Given the differing neurocognitive effects of cocaine and opiates (Basso & Bornstein, 2000; Fernandez-Serrano, Perez-Garcia, & Verdejo-Garcia, 2011), future studies should include participants with both mono- and polysubstance use to characterize better the effects of these substances alone and in combination in the context of HIV infection.

It should be mentioned that HIV, HCV, and substance use are not the only contributors to neurocognitive functioning among people with HIV. While we excluded for severe psychiatric illness including major depression, moderate depression was present in the cohort and was strongly associated with neurocognitive performance. Educational or social factors, additional coinfections, and use of other substances may also have affected cognitive functioning in the present sample, particularly in HIV/HCV-coinfected participants. Additionally, with the emergence of HIV as a chronic condition, HIV-infected individuals increasingly face the neurocognitive effects of aging (Ances et al., 2010; Cherner et al., 2004; Stoff, 2004) and many of the same diseases as the general population, including cardiovascular disease, diabetes, and non–AIDS-defining cancers (Brown et al., 2005; Deeks & Phillips, 2009; Obel et al., 2007; Palella et al., 2006; Phillips, Neaton, & Lundgren, 2008; Powles et al., 2009). Future research should address the impact of these additional cofactors on neurocognitive functioning in the context of HIV.

In conclusion, the present findings support the persistence of brain dysfunction in HIV-infected individuals, particularly those with poor virologic control and comorbid conditions, especially HCV. HIV serostatus appears to have diminished utility as a predictor of neurocognitive impairment when HIV-infected individuals are medically stable, and the present findings therefore emphasize the importance of examining measures of disease severity in relation to neurocognitive function. Our findings also highlight the contribution of comorbid risk factors to neurocognitive functioning in HIV-infected individuals in the HAART era. While remote substance use appears to pose relatively minor neurocognitive risks, HCV coinfection is associated with poorer performance across neurocognitive domains. Future research should focus on longitudinal examination of HIV− and HCV-associated neurocognitive changes, and on relating these changes to neuroimaging and plasma/cerebrospinal fluid markers of brain dysfunction.


This work was supported by the National Institute of Health (Grant R01 MH074368) and the Lifespan/Tufts/Brown Center for AIDS Research (Grant P30 AI042853). This research has been facilitated by the infrastructure and resources provided by the Lifespan/Tufts/Brown Center for AIDS Research and The Miriam Hospital Immunology Center.


The authors have declared that no conflicts of interest exist.


  • Ances BM, Vaida F, Yeh MJ, Liang CL, Buxton RB, Letendre S, Ellis RJ. HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging. Journal of Infectious Diseases. 2010;201(3):336–340. [PMC free article] [PubMed]
  • Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Annals of Internal Medicine. 2006;144(10):705–714. [PubMed]
  • Bajaj JS, Wade JB, Sanyal AJ. Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy. Hepatology. 2009;50(6):2014–2021. [PubMed]
  • Basso MR, Bornstein RA. Neurobehavioural consequences of substance abuse and HIV infection. Journal of Psychopharmacology. 2000;14(3):228–237. [PubMed]
  • Benedict RHB. Brief Visuospatial Memory Test - Revised. Odessa, FL: Psychological Assessment Resources; 1997.
  • Benedict RHB, Schretlen A, Groninger L, Brandt J. Hopkins Verbal Learning Test Revised: Normative data and analysis of inter-form and test-retest reliability. The Clinical Neuropsychologist. 1998;12:43–55.
  • Benedict RHB, Schretlen D, Groninger L, Dobraski M, Shpritz B. Revision of the Brief Visuospatial Memory Test: Studies of normal performance, reliability, and validity. Psychological Assessment. 1996;8(2):145–153.
  • Benton AL, Hamsher K, Sivan AB. Multilingual Aphasia Examination. Iowa City: AJA Associates; 1994.
  • Bica I, McGovern B, Dhar R, Stone D, McGowan K, Scheib R, Snydman DR. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clinical Infectious Diseases. 2001;32(3):492–497. [PubMed]
  • Bornstein RA, Nasrallah HA, Para MF, Whitacre CC, Fass RJ. Duration of illness and neuropsychological performance in asymptomatic HIV infection. Journal of Neuropsychiatry and Clinical Neurosciences. 1994;6(2):160–164. [PubMed]
  • Brandt J, Benedict RHB. Hopkins Verbal Learning Test-Revised (HVLT-R) Lutz, FL: Psychological Assessment Resources, Inc.; 1991.
  • Brew BJ. Evidence for a change in AIDS dementia complex in the era of highly active antiretroviral therapy and the possibility of new forms of AIDS dementia complex. AIDS. 2004;18(Suppl. 1):S75–S78. [PubMed]
  • Brew BJ, Crowe SM, Landay A, Cysique LA, Guillemin G. Neurodegeneration and ageing in the HAART era. Journal of Neuroimmune Pharmacology. 2009;4(2):163–174. [PubMed]
  • Brown TT, Cole SR, Li X, Kingsley LA, Palella FJ, Riddler SA, Dobs AS. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Archives of Internal Medicine. 2005;165(10):1179–1184. [PubMed]
  • Carey CL, Woods SP, Gonzalez R, Conover E, Marcotte TD, Grant I, Heaton RK. Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection. Journal of Clinical and Experimental Neuropsychology. 2004;26(3):307–319. [PubMed]
  • Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, Perronne C. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: A randomized controlled trial. JAMA. 2004;292(23):2839–2848. [PubMed]
  • Chang L, Ernst T, Witt MD, Ames N, Gaiefsky M, Miller E. Relationships among brain metabolites, cognitive function, and viral loads in antiretroviral-naive HIV patients. Neuroimage. 2002;17(3):1638–1648. [PubMed]
  • Chen Y, An H, Zhu H, Stone T, Smith JK, Hall C, Lin W. White matter abnormalities revealed by diffusion tensor imaging in non-demented and demented HIV+ patients. Neuroimage. 2009;47(4):1154–1162. [PMC free article] [PubMed]
  • Cherner M, Ellis RJ, Lazzaretto D, Young C, Mindt MR, Atkinson JH, Heaton RK. Effects of HIV-1 infection and aging on neurobehavioral functioning: Preliminary findings. AIDS. 2004;18(Suppl. 1):S27–S34. [PubMed]
  • Cherner M, Letendre S, Heaton RK, Durelle J, Marquie-Beck J, Gragg B, Grant I. Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine. Neurology. 2005;64(8):1343–1347. [PubMed]
  • Childs EA, Lyles RH, Selnes OA, Chen B, Miller EN, Cohen BA, McArthur JC. Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology. 1999;52(3):607–613. [PubMed]
  • Chung RT, Andersen J, Volberding P, Robbins GK, Liu T, Sherman KE, van der Horst C. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. New England Journal of Medicine. 2004;351(5):451–459. [PMC free article] [PubMed]
  • Clifford DB. HIV-associated neurocognitive disease continues in the antiretroviral era. Topics in HIV Medicine. 2008;16(2):94–98. [PubMed]
  • Clifford DB, Evans SR, Yang Y, Gulick RM. The neuropsychological and neurological impact of hepatitis C virus coinfection in HIV-infected subjects. AIDS. 2005;19(Suppl. 3):S64–S71. [PubMed]
  • Clifford DB, Smurzynski M, Park LS, Yeh TM, Zhao Y, Blair L, Evans SR. Effects of active HCV replication on neurologic status in HIV RNA virally suppressed patients. Neurology. 2009;73(4):309–314. [PMC free article] [PubMed]
  • Cohen RA, Boland R, Paul R, Tashima KT, Schoenbaum EE, Celentano DD, Carpenter CC. Neurocognitive performance enhanced by highly active antiretroviral therapy in HIV-infected women. AIDS. 2001;15(3):341–345. [PubMed]
  • Cohen RA, de la Monte S, Gongvatana A, Ombao H, Gonzalez B, Devlin KN, Tashima KT. Plasma cytokine concentrations associated with HIV/hepatitis C coinfection are related to attention, executive and psychomotor functioning. Journal of Neuroimmunology. 2011;233(1–2):204–210. [PMC free article] [PubMed]
  • Cohen RA, Harezlak J, Gongvatana A, Buchthal S, Schifitto G, Clark U, Navia B. Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes. Journal of Neurovirology. 2010;16(6):435–444. [PMC free article] [PubMed]
  • Cohen RA, Harezlak J, Schifitto G, Hana G, Clark U, Gongvatana A, Navia B. Effects of nadir CD4 count and duration of human immunodeficiency virus infection on brain volumes in the highly active antiretroviral therapy era. Journal of Neurovirology. 2010;16(1):25–32. [PMC free article] [PubMed]
  • Compton WM, Thomas YF, Stinson FS, Grant BF. Prevalence, correlates, disability, and comorbidity of DSM-IV drug abuse and dependence in the United States: Results from the national epidemiologic survey on alcohol and related conditions. Archives of General Psychiatry. 2007;64(5):566–576. [PubMed]
  • Crum NF, Riffenburgh RH, Wegner S, Agan BK, Tasker SA, Spooner KM, Wallace MR. Comparisons of causes of death and mortality rates among HIV-infected persons: Analysis of the pre-, early, and late HAART (highly active antiretroviral therapy) eras. Journal of Acquired Immune Deficiency Syndromes. 2006;41(2):194–200. [PubMed]
  • Cysique LA, Maruff P, Brew BJ. Variable benefit in neuropsychological function in HIV-infected HAART-treated patients. Neurology. 2006;66(9):1447–1450. [PubMed]
  • Cysique LA, Vaida F, Letendre S, Gibson S, Cherner M, Woods SP, Ellis RJ. Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology. 2009;73(5):342–348. [PMC free article] [PubMed]
  • Davis PE, Liddiard H, McMillan TM. Neuropsychological deficits and opiate abuse. Drug and Alcohol Dependence. 2002;67(1):105–108. [PubMed]
  • de la Monte SM, Longato L, Tong M, DeNucci S, Wands JR. The liver-brain axis of alcohol-mediated neurodegeneration: Role of toxic lipids. International Journal of Environmental Research and Public Health. 2009;6(7):2055–2075. [PMC free article] [PubMed]
  • de la Monte SM, Tong M, Nguyen V, Setshedi M, Longato L, Wands JR. Ceramide-mediated insulin resistance and impairment of cognitive-motor functions. Journal of Alzheimer’s Disease. 2010;21(3):967–984. [PMC free article] [PubMed]
  • Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ (Clinical Research Ed.) 2009;338:a3172. [PubMed]
  • Di Sclafani V, Tolou-Shams M, Price LJ, Fein G. Neuropsychological performance of individuals dependent on crack-cocaine, or crack-cocaine and alcohol, at 6 weeks and 6 months of abstinence. Drug and Alcohol Dependence. 2002;66(2):161–171. [PMC free article] [PubMed]
  • Eldreth DA, Matochik JA, Cadet JL, Bolla KI. Abnormal brain activity in prefrontal brain regions in abstinent marijuana users. Neuroimage. 2004;23(3):914–920. [PubMed]
  • Ellis R, Langford D, Masliah E. HIV and antiretroviral therapy in the brain: Neuronal injury and repair. Nature Reviews. Neuroscience. 2007;8(1):33–44. [PubMed]
  • Ersche KD, Clark L, London M, Robbins TW, Sahakian BJ. Profile of executive and memory function associated with amphetamine and opiate dependence. Neuropsychopharmacology. 2006;31(5):1036–1047. [PMC free article] [PubMed]
  • Fals-Stewart W, Schafer J, Lucente S, Rustine T, Brown L. Neurobehavioral consequences of prolonged alcohol and substance abuse: A review of findings and treatment implications. Clinical Psychology Review. 1994;14(8):755–778.
  • Fein G, Torres J, Price LJ, Di Sclafani V. Cognitive performance in long-term abstinent alcoholic individuals. Alcoholism, Clinical and Experimental Research. 2006;30(9):1538–1544. [PMC free article] [PubMed]
  • Fernandez-Serrano MJ, Perez-Garcia M, Schmidt Rio-Valle J, Verdejo-Garcia A. Neuropsychological consequences of alcohol and drug abuse on different components of executive functions. Journal of Psychopharmacology. 2010;24(9):1317–1332. [PubMed]
  • Fernandez-Serrano MJ, Perez-Garcia M, Verdejo-Garcia A. What are the specific vs. generalized effects of drugs of abuse on neuropsychological performance? Neuroscience and Biobehavioral Reviews. 2011;35(3):377–406. [PubMed]
  • Forton DM, Allsop JM, Cox IJ, Hamilton G, Wesnes K, Thomas HC, Taylor-Robinson SD. A review of cognitive impairment and cerebral metabolite abnormalities in patients with hepatitis C infection. AIDS. 2005;19(Suppl. 3):S53–S63. [PubMed]
  • 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;358(9275):38–39. [PubMed]
  • Forton DM, Thomas HC, Murphy CA, Allsop JM, Foster GR, Main J, Taylor-Robinson SD. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology. 2002;35(2):433–439. [PubMed]
  • Golden CJ. Stroop Color and Word Test. Chicago: Stoelting; 1978.
  • Gongvatana A, Cohen RA, Correia S, Devlin KN, Miles J, Clark US, Tashima KT. Impact of Hepatitis C and HIV coinfection on cerebral white matter integrity; Proceedings of the 39th Annual Meeting of the International Neuropsychological Society; Boston, MA. 2011. Feb,
  • Gongvatana A, Schweinsburg BC, Taylor MJ, Theilmann RJ, Letendre SL, Alhassoon OM, Grant I. White matter tract injury and cognitive impairment in human immunodeficiency virus-infected individuals. Journal of Neurovirology. 2009;15(2):187–195. [PMC free article] [PubMed]
  • Grant BF. Prevalence and correlates of drug use and DSM-IV drug dependence in the United States: Results of the National Longitudinal Alcohol Epidemiologic Survey. Journal of Substance Abuse. 1996;8(2):195–210. [PubMed]
  • Green JE, Saveanu RV, Bornstein RA. The effect of previous alcohol abuse on cognitive function in HIV infection. American Journal of Psychiatry. 2004;161(2):249–254. [PubMed]
  • Gruber SA, Silveri MM, Yurgelun-Todd DA. Neuropsychological consequences of opiate use. Neuropsychology Review. 2007;17(3):299–315. [PubMed]
  • Harezlak J, Buchthal S, Taylor M, Schifitto G, Zhong J, Daar E, Navia B. Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS. 2011;25(5):625–633. [PMC free article] [PubMed]
  • Hasin DS, Stinson FS, Ogburn E, Grant BF. Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions. Archives of General Psychiatry. 2007;64(7):830–842. [PubMed]
  • Heaton RK, Clifford DB, Franklin DR, Jr, Woods SP, Ake C, Vaida F, Grant I. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75(23):2087–2096. [PMC free article] [PubMed]
  • Heaton RK, Grant I, Butters N, White DA, Kirson D, Atkinson JH. the HNRC Group. The HNRC 500—neuropsychology of HIV infection at different disease stages. HIV Neurobehavioral Research Center. Journal of the International Neuropsychological Society. 1995;1(3):231–251. [PubMed]
  • Heaton RK, Miller W, Taylor M, Grant I. Revised comprehensive norms for an expanded Halstead-Reitan battery: Demographically adjusted neuropsychological norms for African American and Caucasian adults. Lutz, FL: Psychological Assessment Resources; 2004.
  • Hesselink JR, Tien R, Spoto G, Jernigan TL, Grant I. Accelerated brain atrophy and parenchymal change in patients with AIDS; Proceedings of the International Conference on AIDS; Florence, Italy. 1991. Jun,
  • Hilsabeck RC, Castellon SA, Hinkin CH. Neuropsychological aspects of coinfection with HIV and hepatitis C virus. Clinical Infectious Diseases. 2005;41(Suppl. 1):S38–S44. [PMC free article] [PubMed]
  • Hilsabeck RC, Perry W, Hassanein TI. Neuropsychological impairment in patients with chronic hepatitis C. Hepatology. 2002;35(2):440–446. [PubMed]
  • Hinkin CH, Castellon SA, Levine AJ, Barclay TR, Singer EJ. Neurocognition in individuals co-infected with HIV and hepatitis C. Journal of Addictive Diseases. 2008;27(2):11–17. [PMC free article] [PubMed]
  • Janssen RS, Saykin AJ, Cannon L, Campbell J, Pinsky PF, Hessol NA, Kaplan JE. Neurological and neuropsychological manifestations of HIV-1 infection: Association with AIDS-related complex but not asymptomatic HIV-1 infection. Annals of Neurology. 1989;26(5):592–600. [PubMed]
  • Jernigan TL, Archibald S, Hesselink JR, Atkinson JH, Velin RA, McCutchan JA, Grant I. Magnetic resonance imaging morphometric analysis of cerebral volume loss in human immunodeficiency virus infection. The HNRC Group. Archives of Neurology. 1993;50(3):250–255. [PubMed]
  • Kellogg SH, McHugh PF, Bell K, Schluger JH, Schluger RP, LaForge KS, Kreek MJ. The Kreek-McHugh-Schluger-Kellogg scale: A new, rapid method for quantifying substance abuse and its possible applications. Drug and Alcohol Dependence. 2003;69(2):137–150. [PubMed]
  • Kim WR. The burden of hepatitis C in the United States. Hepatology. 2002;36(5) Suppl. 1:S30–S34. [PubMed]
  • Kløve H. Grooved pegboard. Lafayette, IN: Lafayette Instruments; 1963.
  • Kramer L, Bauer E, Funk G, Hofer H, Jessner W, Steindl-Munda P, Ferenci P. Subclinical impairment of brain function in chronic hepatitis C infection. Journal of Hepatology. 2002;37(3):349–354. [PubMed]
  • Laskus T, Radkowski M, Bednarska A, Wilkinson J, Adair D, Nowicki M, Rakela J. Detection and analysis of hepatitis C virus sequences in cerebrospinal fluid. Journal of Virology. 2002;76(19):10064–10068. [PMC free article] [PubMed]
  • Letendre SL, McCutchan JA, Childers ME, Woods SP, Lazzaretto D, Heaton RK, Ellis RJ. Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders. Annals of Neurology. 2004;56(3):416–423. [PubMed]
  • Letendre SL, Paulino AD, Rockenstein E, Adame A, Crews L, Cherner M, Masliah E. Pathogenesis of hepatitis C virus coinfection in the brains of patients infected with HIV. Journal of Infectious Diseases. 2007;196(3):361–370. [PubMed]
  • Lundqvist T. Cognitive consequences of cannabis use: Comparison with abuse of stimulants and heroin with regard to attention, memory and executive functions. Pharmacology, Biochemistry and Behavior. 2005;81(2):319–330. [PubMed]
  • Martin-Thormeyer EM, Paul RH. Drug abuse and hepatitis C infection as comorbid features of HIV associated neurocognitive disorder: Neurocognitive and neuroimaging features. Neuropsychology Review. 2009;19(2):215–231. [PMC free article] [PubMed]
  • McArthur JC. HIV dementia: An evolving disease. Journal of Neuroimmunology. 2004;157(1–2):3–10. [PubMed]
  • McArthur JC, McClernon DR, Cronin MF, Nance-Sproson TE, Saah AJ, St Clair M, Lanier ER. Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Annals of Neurology. 1997;42(5):689–698. [PubMed]
  • McCrea M, Cordoba J, Vessey G, Blei AT, Randolph C. Neuropsychological characterization and detection of subclinical hepatic encephalopathy. Archives of Neurology. 1996;53(8):758–763. [PubMed]
  • McCutchan JA, Wu JW, Robertson K, Koletar SL, Ellis RJ, Cohn S, Williams PL. HIV suppression by HAART preserves cognitive function in advanced, immune-reconstituted AIDS patients. AIDS. 2007;21(9):1109–1117. [PubMed]
  • Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P, d’Arminio Monforte A, Lundgren JD. Decline in the AIDS and death rates in the EuroSIDA study: An observational study. Lancet. 2003;362(9377):22–29. [PubMed]
  • Monga HK, Rodriguez-Barradas MC, Breaux K, Khattak K, Troisi CL, Velez M, Yoffe B. Hepatitis C virus infection-related morbidity and mortality among patients with human immunodeficiency virus infection. Clinical Infectious Diseases. 2001;33(2):240–247. [PubMed]
  • Moore DJ, Masliah E, Rippeth JD, Gonzalez R, Carey CL, Cherner M, Grant I. Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment. AIDS. 2006;20(6):879–887. [PubMed]
  • Morgello S, Estanislao L, Ryan E, Gerits P, Simpson D, Verma S, Sharp V. Effects of hepatic function and hepatitis C virus on the nervous system assessment of advanced-stage HIV-infected individuals. AIDS. 2005;19(Suppl. 3):S116–S122. [PubMed]
  • Nath A, Maragos WF, Avison MJ, Schmitt FA, Berger JR. Acceleration of HIV dementia with methamphetamine and cocaine. Journal of Neurovirology. 2001;7(1):66–71. [PubMed]
  • O’Malley S, Adamse M, Heaton RK, Gawin FH. Neuropsychological impairment in chronic cocaine abusers. American Journal of Drug and Alcohol Abuse. 1992;18(2):131–144. [PubMed]
  • Obel N, Thomsen HF, Kronborg G, Larsen CS, Hildebrandt PR, Sorensen HT, Gerstoft J. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: A population-based cohort study. Clinical Infectious Diseases. 2007;44(12):1625–1631. [PubMed]
  • Palella FJ, Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, Holmberg SD. Mortality in the highly active antiretroviral therapy era: Changing causes of death and disease in the HIV outpatient study. Journal of Acquired Immune Deficiency Syndromes. 2006;43(1):27–34. [PubMed]
  • Pascual-Leone A, Dhuna A, Anderson DC. Longterm neurological complications of chronic, habitual cocaine abuse. Neurotoxicology. 1991;12(3):393–400. [PubMed]
  • Paul RH, Ernst T, Brickman AM, Yiannoutsos CT, Tate DF, Cohen RA, Navia BA. Relative sensitivity of magnetic resonance spectroscopy and quantitative magnetic resonance imaging to cognitive function among nondemented individuals infected with HIV. Journal of the International Neuropsychological Society. 2008;14(5):725–733. [PubMed]
  • Paul RH, Yiannoutsos CT, Miller EN, Chang L, Marra CM, Schifitto G, Navia BA. Proton MRS and neuropsychological correlates in AIDS dementia complex: Evidence of subcortical specificity. Journal of Neuropsychiatry and Clinical Neurosciences. 2007;19(3):283–292. [PubMed]
  • Perry W, Hilsabeck RC, Hassanein TI. Cognitive dysfunction in chronic hepatitis C: A review. Digestive Diseases and Sciences. 2008;53(2):307–321. [PubMed]
  • Pezawas LM, Fischer G, Diamant K, Schneider C, Schindler SD, Thurnher M, Kasper S. Cerebral CT findings in male opioid-dependent patients: Stereological, planimetric and linear measurements. Psychiatry Research. 1998;83(3):139–147. [PubMed]
  • Phillips AN, Neaton J, Lundgren JD. The role of HIV in serious diseases other than AIDS. AIDS. 2008;22(18):2409–2418. [PMC free article] [PubMed]
  • Pomara N, Crandall DT, Choi SJ, Johnson G, Lim KO. White matter abnormalities in HIV-1 infection: A diffusion tensor imaging study. Psychiatry Research. 2001;106(1):15–24. [PubMed]
  • Powles T, Robinson D, Stebbing J, Shamash J, Nelson M, Gazzard B, Bower M. Highly active antiretroviral therapy and the incidence of non-AIDS-defining cancers in people with HIV infection. Journal of Clinical Oncology. 2009;27(6):884–890. [PubMed]
  • Radloff LS. The CES-D Scale: A self-report depression scale for research in the general population. Applied Psychological Measurement. 1977;1(3):385–401.
  • Reitan RM. Trail Making Test. Tucson, AZ: Reitan Neuropsychology Laboratory; 1992.
  • Rippeth JD, Heaton RK, Carey CL, Marcotte TD, Moore DJ, Gonzalez R, Grant I. Methamphetamine dependence increases risk of neuropsychological impairment in HIV infected persons. Journal of the International Neuropsychological Society. 2004;10(1):1–14. [PubMed]
  • Robertson KR, Robertson WT, Ford S, Watson D, Fiscus S, Harp AG, Hall CD. Highly active antiretroviral therapy improves neurocognitive functioning. Journal of Acquired Immune Deficiency Syndromes. 2004;36(1):562–566. [PubMed]
  • Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, Wu J, Ellis RJ. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS. 2007;21(14):1915–1921. [PubMed]
  • Ryan EL, Morgello S, Isaacs K, Naseer M, Gerits P. Neuropsychiatric impact of hepatitis C on advanced HIV. Neurology. 2004;62(6):957–962. [PMC free article] [PubMed]
  • Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, McArthur JC, Epstein L. HIV-associated cognitive impairment before and after the advent of combination therapy. Journal of Neurovirology. 2002;8(2):136–142. [PubMed]
  • Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus: A cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clinical Infectious Diseases. 2002;34(6):831–837. [PubMed]
  • Stern RA, Arruda JE, Somerville JA, Cohen RA, Boland RJ, Stein MD, Martin EM. Neurobehavioral functioning in asymptomatic HIV-1 infected women. Journal of the International Neuropsychological Society. 1998;4(2):172–178. [PubMed]
  • Stoff DM. Mental health research in HIV/AIDS and aging: Problems and prospects. AIDS. 2004;18(Suppl. 1):S3–S10. [PubMed]
  • Tarter RE, Hegedus AM, Van Thiel DH, Schade RR, Gavaler JS, Starzl TE. Nonalcoholic cirrhosis associated with neuropsychological dysfunction in the absence of overt evidence of hepatic encephalopathy. Gastroenterology. 1984;86(6):1421–1427. [PMC free article] [PubMed]
  • Thompson PM, Dutton RA, Hayashi KM, Toga AW, Lopez OL, Aizenstein HJ, Becker JT. Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD41 T lymphocyte decline. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(43):15647–15652. [PubMed]
  • Tozzi V, Balestra P, Bellagamba R, Corpolongo A, Salvatori MF, Visco-Comandini U, Narciso P. Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: Prevalence and risk factors. Journal of Acquired Immune Deficiency Syndromes. 2007;45(2):174–182. [PubMed]
  • Tozzi V, Balestra P, Lorenzini P, Bellagamba R, Galgani S, Corpolongo A, Narciso P. Prevalence and risk factors for human immunodeficiency virus-associated neurocognitive impairment, 1996 to 2002: Results from an urban observational cohort. Journal of Neurovirology. 2005;11(3):265–273. [PubMed]
  • Valcour VG, Shikuma CM, Watters MR, Sacktor NC. Cognitive impairment in older HIV-1-seropositive individuals: Prevalence and potential mechanisms. AIDS. 2004;18(Suppl. 1):S79–S86. [PMC free article] [PubMed]
  • Valcour VG, Yee P, Williams AE, Shiramizu B, Watters M, Selnes O, Sacktor N. Lowest ever CD4 lymphocyte count (CD4 nadir) as a predictor of current cognitive and neurological status in human immunodeficiency virus type 1 infection–The Hawaii Aging with HIV Cohort. Journal of Neurovirology. 2006;12(5):387–391. [PubMed]
  • van Gorp WG, Wilkins JN, Hinkin CH, Moore LH, Hull J, Horner MD, Plotkin D. Declarative and procedural memory functioning in abstinent cocaine abusers. Archives of General Psychiatry. 1999;56(1):85–89. [PubMed]
  • Weber R, Sabin CA, Friis-Moller N, Reiss P, El-Sadr WM, Kirk O, Lundgren JD. Liver-related deaths in persons infected with the human immunodeficiency virus: The D:A:D study. Archives of Internal Medicine. 2006;166(15):1632–1641. [PubMed]
  • Wechsler D. Wechsler Adult Intelligence Scale-III (WAIS-III) San Antonio, TX: The Psychological Corporation; 1997.
  • Weissenborn K, Krause J, Bokemeyer M, Hecker H, Schuler A, Ennen JC, Boker KW. Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy. Journal of Hepatology. 2004;41(5):845–851. [PubMed]
  • Wilkinson J, Radkowski M, Laskus T. Hepatitis C virus neuroinvasion: Identification of infected cells. Journal of Virology. 2009;83(3):1312–1319. [PMC free article] [PubMed]
  • Woods SP, Moore DJ, Weber E, Grant I. Cognitive neuropsychology of HIV-associated neurocognitive disorders. Neuropsychology Review. 2009;19(2):152–168. [PMC free article] [PubMed]