The Central Nervous System Manifestations of HIV-1 Infection in the Combination Antiretroviral Therapy Era

Abstract

Following the introduction of effective therapies to treat human immunodeficiency virus (HIV-1) infection in the mid-1990s, a dramatic reduction in the incidence of severe HIV-1 associated brain disease was observed. In spite of such advances however, milder forms of HIV-1 associated neurocognitive disorders (HAND) have become increasingly apparent in recent years and can reduce the cognitive function, quality of life and overall survival of those affected. Coinfection with viral hepatitis C (HCV) and poor central nervous system (CNS) penetration of antiretroviral drugs may be risk factors for this condition. This thesis examines the following two hypotheses: Use of antiretroviral drugs with greater CNS penetration is associated with greater improvements in cerebral function parameters in HIV-1 infected subjects Acquisition of acute HCV coinfection is associated with a deterioration of cerebral function parameters in HIV-1 infected subjects These hypotheses were tested in a series of clinical studies. First, retrospective data from the largest UK cohort study of adult HIV-1 infected subjects were analysed to assess the impact of antiretroviral therapy CNS penetration upon HIV-associated brain disease incidence and survival between 1996 and 2008. Second, prospective changes to cerebral function parameters were assessed in HIV-1 infected subjects switching to novel antiretroviral regimens with differing CNS penetration via the use of longitudinal cerebral proton spectroscopy and computerised cognitive assessments. In order to investigate the second hypothesis, a cross-sectional study was performed to assess cognition in HIV-1 infected subjects, with and without acute HCV coinfection. Finally, the presence of neuronal damage, neuronal inflammation and in vivo microglial cell activation in individuals with chronic HIV-1 and acute HCV coinfection were investigated in case-control studies utilising cerebral proton spectroscopy and positron emission tomography. Results demonstrated that in some controlled settings, novel antiretroviral switching strategies involving simplification to darunavir-containing triple or monotherapy or intensification with maraviroc, are associated with improvements to parameters of cerebral function. No evidence that the widespread use of regimens with higher CSF penetration effectiveness scores is associated with reduced incidence of HIV-1 associated CNS opportunistic diseases was found. It was also demonstrated that cerebral disturbance and a deterioration of cerebral function parameters is associated with acute hepatitis C (HCV) coinfection via impairment of executive functioning and increased cerebral metabolites. No association between microglial cell activation and acute HCV/HIV coinfection was found.