Hepatitis C virus co-infection increases neurocognitive impairment severity and risk of death in treated HIV/AIDS

Abstract

Previous studies have reported that hepatitis C virus (HCV) co-infection worsens neurocognitive status among individuals with human immunodeficiency virus (HIV)-1 infection. We assessed the prevalence of neurologic disorders and the severity of HIV-associated neurocognitive impairment among HIV-infected individuals in two centralized HIV clinics in Alberta, Canada from 1998 to 2010 based on their HCV serostatus. Of 456 HIV-infected persons without concurrent substance abuse, 91 (20.0%) were HCV seropositive. Of 58 neurologic disorders identified in the cohort, HIV/HCV co-infected individuals exhibited a higher prevalence of multiple neurologic disorders compared to HIV-infected individuals (60.4% vs. 46.6%, p < 0.05) and a higher frequency of seizures (28.6% vs. 17.8%, p < 0.05). Unlike HIV mono-infected persons, the risk of seizures was independent of immune status in HIV/HCV co-infected individuals (p < 0.05). Symptomatic HIV-associated neurocognitive disorders (sHAND) were more severe among HIV/HCV co-infected persons (p < 0.05). HCV co-infection was associated with an increased mortality rate (24.2% vs. 14.5%, p < 0.05) with a mortality hazard ratio of 2.38 after adjusting for demographic and clinical variables. Our results indicate that the presence of HCV co-infection among HIV-infected individuals increased neurologic disease burden and risk of death, underscoring HCV's capacity to affect the nervous system and survival of HIV-infected persons.

Introduction

Combination antiretroviral therapy (cART) has been proven immensely successful in restoring the immune status of persons infected with human immunodeficiency virus type 1 (HIV-1) [1]. Nevertheless, neurologic disorders remain a major disease burden and are associated with a reduced survival among HIV-infected persons [2]. HIV-related primary brain disorders have been termed AIDS dementia complex, HIV-associated encephalopathy or HIV-associated dementia and usually defined by neurocognitive, neurobehavioral and motor disabilities [3]. However, the diagnoses of neurocognitive impairments in HIV/AIDS have recently been refined to encompass symptomatic HIV-associated dementia and minor neurocognitive disorder as well as asymptomatic neurocognitive disorder [4]. These diagnoses are largely based on neuropsychological performance coupled with clinical aspects. Due to similar routes of viral transmission, especially intravenous drug use (IDU), 30% of HIV-infected individuals (4–5 million) globally are co-infected with hepatitis C virus (HCV) [5]. HIV/HCV co-infection is associated with worse clinical outcomes of both diseases in terms of systemic disease progression and mortality [6], [7].

HCV is a member of the Flaviviridae family, which includes several neurotropic viruses such as West Nile virus (WNV), St. Louis encephalitis virus and Japanese encephalitis virus [8]. The notion that HCV can invade the central nervous system (CNS) is supported by detection of HCV-specific transcripts and proteins in post-mortem brains of HIV/HCV co-infected patients [9], [10], [11]. HCV-encoded RNA is also present in cerebrospinal fluid [12] and peripheral nerves of HCV-infected patients [13]. Recently, the most abundant HCV-encoded protein, Core, has been shown to induce neuroinflammation and cause neuronal death [14]. Indeed, neuropsychological studies using various test batteries have reported different cognitive domains to be impaired in HIV/HCV co-infected individuals compared with HIV mono-infected persons [15], [16], [17], [18], while similar levels of overall neurocognitive impairment between groups were found [19], [20]. The level of N-acetyl aspartate, a neuronal marker, in the brains of HCV-infected individuals was lower than in matched controls' brains, as measured by MRS and was inversely correlated with neurocognitive impairment (NCI) [21]. Recently, glial activation and increased abnormal white matter were reported in brains of HCV-infected individuals [22], [23]. The greater prevalence and severity of fatigue and depression were also reported in individuals with HCV seropositivity [15], [24]. In contrast, distal sensory polyneuropathy (DSP), the most common neurological disorder in HIV-infected persons, was not associated with HCV seropositivity and active HCV replication in HIV/HCV co-infected persons [25], [26]. However, the overall prevalence of different neurologic disorders in individuals with HIV and HCV co-infection remains uncertain. The infection of glial cells with HCV and ensuing neuroinflammation induced by HCV infection lead us to hypothesize that HCV co-infection might increase the risk and severity of neurologic disorders in HIV-infected patients. Since HCV infection increases mortality among HIV/HCV co-infected individuals [6], [7] and neurologic disorders have been linked to reduced survival of treated HIV-infected individuals [2], [27], [28], we also investigated whether HCV was a risk factor for mortality in HIV/HCV co-infected individuals with neurologic disease.