Abstract.
Background.

Microglial cell activation and cerebral function impairment are described in both chronic hepatitis C viral (HCV) and Human-Immune-Deficiency viral (HIV) infections. The aim of this study was to investigate the effect of acute HCV infection upon cerebral function and microglial cell activation in HIV-infected individuals.

Methods.

A case-control study was conducted. Subjects with acute HCV and chronic HIV coinfection (aHCV) were compared to matched controls with chronic HIV monoinfection (HIVmono). aHCV was defined as a new positive plasma HCV RNA within 12 months of a negative RNA test. Subjects underwent neuro-cognitive testing (NCT), cerebral proton magnetic resonance spectroscopy (1H-MRS) and positron emission tomography (PET) using a 11C-radiolabeled ligand (PK11195), which is highly specific for translocator protein 18 kDA receptors on activated microglial cells. Differences between cases and controls were assessed using linear regression modelling.

Results.

Twenty-four aHCV cases completed NCT and 1H-MRS, 8 underwent PET. Of 57 HIVmono controls completing NCT, 12 underwent 1H-MRS and 8 PET. Subjects with aHCV demonstrated on NCT, significantly poorer executive function (mean (SD) error rate 26.50(17.87) versus 19.09(8.12), p = 0.001) and on 1H-MRS increased myo-inositol/creatine ratios (mI/Cr, a marker of cerebral inflammation) in the basal ganglia (ratio of 0.71(0.22) versus 0.55(0.23), p = 0.03), compared to subjects with HIVmono. On PET imaging, no difference in 11C-PK11195 binding potential (BP) was observed between study groups (p>0.10 all cerebral locations), however lower BPs were associated with combination antiretroviral therapy (cART) use in the parietal (p = 0.01) and frontal (p = 0.03) cerebral locations.

Discussion.

Poorer cognitive performance and disturbance of cerebral metabolites are observed in subjects with aHC,V compared to subjects with HIVmono. Higher 11C-PK11195 BP was not observed in subjects with aHCV, but was observed in subjects not on cART.

Introduction.

Central nervous system disturbances are well described in patients with chronic HIV infection and more recently, in those with chronic hepatitis C (HCV) infection in the absence of significant liver disease[1]–[3]. Abnormalities, compared to matched control populations, demonstrable using cerebral function measures such as neurocognitive testing (NCT) and proton magnetic resonance spectroscopy (1H MRS) have been shown in both patient groups [4], [5]. Such cerebral deficits may be greater in individuals coinfected with HIV and chronic HCV, compared to individuals with HIV monoinfection [6]–[9]. Both viruses can be identified in cerebrospinal fluid and brain tissue [9]–[11] and although the pathophysiology of these cerebral disturbances remain unclear, microglial cell activation has been proposed as a promoter of neurodegeneration and inflammation in both HIV-associated encephalopathy [12] and chronic HCV-associated cognitive decline [13].

The isoquinoline PK11195 is a highly specific, high-affinity ligand for translocator protein 18 kDA receptors on activated microglial cells. PK11195 can be radio-labeled with carbon 11 (11C) and injected as a tracer during cerebral positron emission tomography (PET) scanning to provide non-invasive, quantification of microglial cell activity at a cellular level. This technique has been histologically validated in animals [14], [15] and humans [16] and used to demonstrate microglial activation in a variety of human neurological disorders, including in patients with chronic HCV in the presence or absence of cirrhosis [17]–[20]. To date, increased binding of PK11195 has been demonstrated only in HIV-infected subjects with severe HIV encephalopathy [21], with increased binding not reported in asymptomatic HIV-infected subjects or in those with mild cognitive deficits [22].

The impact of acute HCV infection acquisition upon cerebral function parameters remains poorly understood. Secondary to a recent epidemic of acute HCV infection in HIV-infected men who have sex with men, this phase of infection is now frequently identified in clinical practice [23], [24]. Earlier work from our group [25] identified a reduction in inflammatory cerebral metabolites in the basal ganglia of 10 subjects with acute HCV and chronic HIV infection. The aim of this study, was to further elucidate any changes in cerebral function observed in subjects during acute HCV infection via the assessment of cognitive performance and cerebral metabolites and to assess for any evidence of increased microglial cell activation via PET imaging.