HIV and HCV co-infection: Neurological Manifestations and Implications
The number of people estimated to be infected with Hepatitis C virus (HCV) worldwide is a staggering 200 million.1,2 An estimated 40 million people are infected with HIV. Both these viruses have been shown to infect lymphocytes and to cause serious damage to the peripheral and central nervous systems (PNS and CNS). The neurological manifestations of HIV have been well delineated, because researchers have had 20 years to study HIV neuropathogenesis. However, the neurological manifestations of HCV have been less well characterized and reported, in part because the virus has been identified only for one decade. In time, the neurological manifestations of HCV are certain to be considered as very important extrahepatic complications of this virus, just as the neurological manifestations of HIV are seen to be of critical importance among HIV's complications. Moreover, because the routes of transmission of HIV and HCV are similar, it is estimated that between 9% and 40% of HIV-infected individuals are co-infected with HCV, with an average estimate of between 25% and 30%. The highest percentages of co-infection have been found in injection drug users (IDUs) and hemophiliacs (52% to 90% and 60% to 85%, respectively).1,2 Many of our patients have multiple risk factors for transmission of both these viruses, mandating that we test for HCV regularly in HIV-infected patients. While both HIV and HCV clearly have been shown to cause neurological complications, the exact nature of how these viruses may interact to promote or amplify neurological disease is not well understood. This paper reviews the less well reported neurological complications of HCV and discusses the neurological implications of HIV and HCV co-infection.

It is agreed that HIV penetrates the CNS early in the course of infection. The same may be true for HCV. Fujita et al reported a case of acute viral encephalitis with subsequent discovery of acute HCV infection.3 Two teams have reported the presence of HCV by quantitative polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) of HCV-infected patients.4,5 Because, in most of the cases, the HCV genotype was the same in the individual patient's plasma and CSF, it was postulated that the virus was of plasma origin. The mechanism of transport of HCV from the systemic circulation into the CNS is likely to be similar to that of HIV because both viruses have been shown to infect monocytes6 and these cells can cross the blood­brain barrier.

Direct productive infection with HCV. often associated with mixed cryoglobulinemia, has been shown to cause numerous CNS diseases, even in the absence of hepatic failure. The presumed mechanism is a vasculitis associated with cryoglobulinemia and multiple ischemic infarcts. Encephalopathy ranging from minor confusion to severe cognitive-motor dysfunction has been described.7­9 In 1998, Origgi and colleagues described three patients with chronic HCV infection and cryoglobulinemia who complained of mild CNS problems, including confusion and disequilibrium. Magnetic Resonance Imaging (MRI) of these patients showed small hyperintensities consistent with ischemic lesions.8

In Heckmann et al's 1999 review of a small series of HCV- infected patients showing neurological manifestations, a patient with systemic vasculitis associated with cryoglobulinemia is described who progressed from apathy to severe drowsiness with myoclonic jerks and multiple pyramidal tract signs. MRI showed increased prolonged spin echo signal diffusely throughout the deep white matter that by description resembles that of HIV-associated leukoencephalopathy seen in HIV-associated dementia.10 Cerebrovascular accidents (CVAs, commonly known as strokes), including hemorrhagic events, also have been described in HCV-infected persons.11,12 In addition, some cases of HCV CNS disease appear to be unrelated to vasculitis. Bolay et al reported a case in 1996 of severe progressive encephalomyelitis associated with HCV where postmortem analysis of brain and spinal cord showed perivascular lymphocytic cuffing and diffuse infiltration and neuronal loss. HCV was detected by PCR in all of these specimens.13

Pure myelopathies (spinal cord dysfunction) have also been associated with HCV. In 1994, Hino et al reported on 13 patients with a progressive spastic paraparesis. These patients were seronegative for HIV, HTLV-I, or HTLV-II. They all had evidence for chronic Hepatitis B virus infection, and five also had detectable HCV. These patients were studied at a time when HCV PCR was imprecise, and it is not clear whether it was the HBV or HCV that caused the myelopathies.14 This year, Spencer and Forno described a case of severe HCV where the myelopathy on postmortem was correlated with dramatic vacuolation of the spinal cord. Once again, this finding is analogous to that seen with HIV-associated vacuolar myelopathy.15

Similarities between some of the reported cellular metabolic abnormalities seen in HIV and HCV also are striking. Levels of toxic cytokines, such as TNF-alpha and IFN-gamma, are elevated in both these viral infections. These pro-inflammatory cytokines have been implicated in the multifactorial etiology of HIV encephalopathy.16,17 Additionally, Quinolinic acid (Quin) is a neurotoxic metabolite of the amino acid tryptophan that is found in elevated concentrations in HIV-infected patients and is also implicated in HIV encephalopathy. Quin is both a direct neurotoxin and an NMDA receptor agonist that precipitates neuronal apoptosis and cell death. Levels of Quin are elevated in patients with HCV infection.18

We were not able to find any references that reported mutual up-regulation of HIV and HCV, a process that has been reported in co-infection with HIV and other viruses, most notably Cytomegalovirus (CMV), Epstein­Barr virus (EBV), Human Herpes virus-8 (HHV-8), and JC virus. However, if both HIV and HCV independently cause neurological disease via similar mechanisms, their effect on the nervous system must not be underestimated.

HCV has also been associated with neuropsychiatric abnormalities such as depression and mood disorders.19 However, it has been difficult in some cases to differentiate the contribution of HCV versus the neuropsychiatric complications caused by the most common treatment for HCV infection, IFN-alpha.20 Thomas et alevaluated chronic fatigue associated with HCV infection in 1999. They performed formal neuropsychological testing in 19 patients with mild HCV infection and performed MR Spectroscopy (MRS) on three groups: (1) an additional 27 similar patients; (2) matched controls who had only chronic hepatitis B; and (3) a set of healthy controls. Only the HCV- infected group showed neuropsychological abnormalities. Additionally, the MRS in the HCV group showed an increase in the levels of choline to creatine, whereas the hepatitis B and healthy control groups had normal MRS scans. These MRS changes are similar to those reported in HIV-associated dementia.21

Most of the literature reporting on the neurological manifestation of HCV pertains to the peripheral nervous system and describes painful neuropathies. However, rare cases of HCV- associated myopathy have also been reported,22 and one recent report described an association with fibromyalgia.23 The most common type of peripheral neuropathy associated with HCV is that associated with essential mixed cryoglobulinemia (EMC.) Ripault et al reported in 1999 on a series of 36 patients with HCV and found that seven (19%) had a peripheral neuropathy associated with HCV; 8% had EMC-associated peripheral neuropathy. While these patients did not have HIV, it was not clear whether ethanol abuse contributed to the characteristic findings of axonopathy with some minimal demyelination and vasculitic lesion seen on electromyography with nerve conduction velocity testing (EMG/NCV) and sural nerve biopsies.24 In a similar series, Zaltron et al reported in 1998 on 89 patients with HCV who underwent EMG/NCV testing. They found that 37% of patients showed electrical evidence of peripheral neuropathy. However one-third of these patients did not have evidence of cryoglobulinemia.25 Bonetti et al reported in 1999on five HCV patients with EMC-associated peripheral neuropathy. In all five, HCV was detected in nerve biopsy by PCR and was localized to the epineurial cells by reverse transcription PCR.26 In 1997, Caudal and associates published a case report of a patient with chronic HCV and painful sensory neuropathy where no other etiology was evident. This patient also had detectable HCV by PCR in his CSF indicating both CNS and PNS productive HCV infection.27 Two independent studies reported that HCV subtype 1b correlated more significantly with peripheral neuropathy.28,29 Both plasma exchange and corticosteroids have been used with some success to treat these patients when they have evidence of either vasculitis or demyelination.30,31

There have been rare reported cases of cryoglobulin associated peripheral neuropathy in HIV infection without HCV.32 However, most cases of HIV-related peripheral neuropathy are due to HIV alone, "D" nucleoside analogue toxicity, or a combination of these factors. Because painful sensory neuropathy is so common in HIV infection (it occurs in 30% to 35% of cases), intuitively it seems that the combined effects of HIV and HCV on peripheral nerves would be worse than the effect of either viral infection alone. However, no study to date has examined the effects of co-infection with HIV and HCV on the PNS and CNS, and due to the multiplicity of confounding factors that could cause neuropathy in this subject sample, such a study would be inherently complex. All other types of peripheral neuropathies including Guillain­Barre, chronic inflammatory demyelinating polyneuropathy and mononeritis have also been reported, infrequently, in association with HCV infection.33­36

Longitudinal studies that include careful neurological examination of patients who are HCV-infected and who are co-infected with HCV and HIV are needed if we are to understand the effects of co-infection on the nervous system. We must heed the lessons learned from studying HIV and commence these studies now so that we do not waste another decade in our quest for answers. By doing so, we will determine whether the effects of each virus are additive or whether they augment one another in their attacks on the nervous system, and we can adopt treatment strategies as newer drugs emerge. We face many dilemmas in studying these patients, including the fact that the most common treatment (IFN-alpha) can itself cause encephalopathy and peripheral neuropathy (though usually self- limited to the course of treatment).19,37 Many co-infected patients have CNS and PNS damage from the effects of chronic use of ethanol and injection drugs. Additionally, so many of the medications used to treat HIV are potentially hepatotoxic, and end-stage liver disease with hyperbilirubinemia and hyperammonemia often make neurological and neuropsychological assessment difficult. In spite of these obstacles, we must begin to study these co-infected patients, paying particular attention to potentially devastating and life-impacting neurological complications.

The authors wish to acknowledge Ms. Teresa Hanbey, Director of the Hepatitis C Outreach Project, for her assistance in the preparation of this manuscript.

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