On blood and cerebrospinal fluid biomarkers of HIV-1 in the central nervous system

Abstract

Infection of the central nervous system (CNS) occurs early after transmission of human immunodeficiency virus (HIV), establishing a chronic infection which, if left untreated, can cause neurocognitive impairment in people living with HIV (PWH). In this thesis, biomarkers in blood and cerebrospinal fluid (CSF) were used to investigate aspects of pathogenesis, response to antiretroviral treatment (ART), and effects of treatment switch regarding HIV infection of the CNS. In paper I, the astroglial biomarker YKL-40 was measured in CSF in 120 PWH (7 with HIV-associated dementia, 85 untreated asymptomatic, and 28 on ART). YKL-40 was strongly correlated with neurofilament light (NfL), a biomarker of neuronal injury, implicating astrocyte activation as a part of the neuropathogenesis of HIV. In paper II, NfL, together with a panel of biomarkers of neuroinflammation, was measured in longitudinal archived CSF samples from 99 neuroasymptomatic PWH initiating ART. We found that all biomarkers declined significantly after three as well as twelve months of treatment, most pronouncedly in participants with elevated NfL levels at baseline. Paper III evaluated switching from one prodrug of the antiretroviral drug tenofovir; tenofovir disoproxil fumarate (TDF), to tenofovir alafenamide fumarate (TAF), a newer prodrug associated with less renal and bone density side effects. NfL was measured in plasma at baseline and after 24 and 84 weeks in 272 participants who switched to TAF and 144 continuing with TDF. There was a small but significant decrease of plasma NfL in the TAF group, resulting in significantly lower plasma NfL levels compared to the TDF group, after 84 weeks. In paper IV, treatment simplification to a two-drug regimen of dolutegravir and lamivudine was evaluated in 113 PWH by measuring plasma NfL before and one year after switch and by analyzing CSF in a subgroup of 20 participants with a sensitive multiplex immunoassay of 127 biomarkers. We found no significant changes in NfL or inflammatory biomarkers, indicating the CNS safety of switch to this regimen. In conclusion, astrocyte activation is associated with neuronal injury in HIV, ART effectively reduces signs of neuroinflammation and neuronal injury and regimen switch to both TAF and dolutegravir/lamivudine appear safe regarding CNS.