Thursday, December 30, 2010

Does Acute HCV Affect the Central Nervous System in HIV-1 Infection?

Does Acute HCV Affect the Central Nervous System in HIV-1 Infection?

Authors and Disclosures

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Abstract and Introduction
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Acute HCV infection is a condition that has hitherto been unrecognized by medicine, as HCV-infected individuals normally present after a lag period of many years following initial infection. Given the rarity of its presentation, this is the first study to assess the effects of acute HCV infection on the central nervous system. We have observed significant reductions in RBG mI/Cr ratio in HIV-1 infected subjects with acute HCV infection, compared with that in matched groups of HIV-1 infected subjects without HCV infection and in healthy controls. Furthermore, significant abnormalities in neurocognitive function were observed.

The fall in mI/Cr ratio that we have observed was predominantly secondary to a reduction in mI in subjects with acute hepatitis C, although there was a trend towards a raised Cr in this group also [mI (±SD) of 121 (±13) vs 129 (±11) and 130 (±10) and Cr (±SD) of 44 (±8) vs 38 (±4), 39 (±5) in groups 1 vs 2 and 3, P = 0.049 and 0.143 respectively]. Other groups have described altered cerebral metabolite patterns in chronic HCV, rather than acute HCV, with differing results including elevation of basal ganglia and central white matter Cho,[2,16,29] reductions in grey and white matter NAA[5,29] and, of note, increases in FWM mI/Cr ratio.[20]

We have utilized the jMRUI software package which uses the AMARES algorithm to analyse our data.[27] This algorithm has several advantages such as the programming of prior knowledge to analyse data which reduces operator-dependent variability.[30] Forton et al.,[20] utilizing a similar analytical method, also observed changes in mI/Cr ratio in patients with chronic HCV, but reported an increase in this ratio in the FWM, rather than the reductions in mI/Cr that we found in patients with acute HCV. mI is an osmosensitive glial marker and plays a crucial role in cell volume regulation.[31] Organic osmolytes, such as mI, accumulate inside the cell in response to cell shrinkage, and are rapidly released in response to cell swelling via osmoregulated membrane channels.[32,33] Our findings are novel in patients with acute viral infections, as a low mI/Cr ratio has previously been observed only in patients with end-stage liver disease with established cirrhosis and hepatic encephalopathy, where there are varying degrees of cerebral oedema in response to the presence of unfiltered circulating toxins, such as ammonia, with subsequent regulatory lowering of mI levels in an effort to maintain astrocyte osmotic equilibrium, as the brain swells.[34] Clearly, this is not the mechanism in our cohort with documented acute HCV infection, who may be up to 30 years away from developing HCV-related end-stage liver disease, if their viral infection persisted. We hypothesize that the reduction in mI/Cr ratio we have observed may be an early response to the direct effects of HCV on the CNS and could suggest an initial cellular swelling as part of the acute neuroinflammatory response to the presence of the HCV.

Previous reports have described significant changes in cerebral metabolite patterns in HIV-1 infected subjects with AIDS Dementia Complex, such as an increase in mI in FWM.[35,36] We did not observe any differences between groups 2 and 3 in our study, which is likely to reflect the exclusion of any baseline neurological disease from inclusion in this study. Furthermore, the mean CD4+ lymphocyte count in the HIV-1 mono-infected group was high at 392 cells/μL (SD ± 124), with 60% of subjects on ART; both factors associated with a reduced incidence of HIV-1 related brain injury.

In HIV-1 non-infected subjects with chronic HCV infection, studies have suggested that up to one-third of subjects have CNS dysfunction.[20] We have observed a mI/Cr ratio below the lowest value in 50% of subjects in our control population. Although small numbers are represented, the relatively high proportion of subjects with evidence of HCV-associated CNS disease may be related to the acute nature of the infection, with a more aggressive inflammatory response, or viral replication, or may reflect a greater propensity for CNS dysfunction in HIV-1 infected subjects. It has been postulated that the effects of HCV on the CNS may be because of cerebral immune activation[37] or direct viral replication.[15] In the context of HIV disease, both of these processes may occur at increased rates.

Chronic fatigue has been well described in chronic HCV infection.[29] In this study, we describe a significant reduction in the monitoring domain with a large effect size of this association (r-value >0.28).[28] This may be associated with fatigue and an inability to concentrate on a task in the setting of acute HCV. No significant associations were observed directly between this cognitive test and cerebral metabolites, which may be related to small study numbers.

Abnormal cerebral metabolism has been documented in recreational drug-dependent subjects[38] and may confound results in studies assessing CNS function in HCV. We therefore excluded subjects currently using recreational drugs, thereby eliminating this bias and we excluded subjects with other sexually transmitted infections which are known to cause CNS disease, such as early syphilis.

This study is the first report to describe significant effects of acute HCV infection on the CNS in HIV-1 infected subjects. Clinicians should be vigilant for the early onset of the CNS effects associated with HCV infection, particularly in those co-infected with HIV. Further studies are required to put these results into context, including cerebral positron emission tomography with the specific ligand [11C](R)-PK11195 as a marker of microglial activation,[39] and there is a need for treatment programmes which monitor viral eradication in acute HCV infection to incorporate assessment of these imaging and psychometric parameters to look for resolution over time of the CNS observations that we have reported.
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