12/7/17 Disclosures UPDATES IN HIV NEUROLOGY Felicia Chow, MD, MAS • I have nothing to disclose. University of California, San Francisco December 7, 2017 Zayyad et al. Curr HIV/AIDS Rep 2015 Brain Compartment Overall proportion of persons living with HIV with cognitive impairment has not changed with ART Clinical case: I saw a 54-year-old patient in clinic last week who was complaining of memory impairment for at least 1 year. He has been positive for 15 years and virologically suppressed for over a decade. Comorbidities include mild depression treated with sertraline, hypertension, and a history of meth use. Approximately half of persons living with HIV have evidence of cognitive impairment, though severe symptoms are much less common. Saylor et al. Nat Rev Neurol 2016 1
12/7/17 Multiple mechanisms likely contribute to CNS injury HIV entry into the CNS occurs early in infection and cognitive impairment in HIV CNS injury early in infection not reversed by ART Inadequate antiretroviral Persistent, compartmentalized exposure or toxicity within CNS CNS infection Ongoing CNS immune Neurodegeneration of activation aging Co-morbidities (substance Inflammation and immune abuse, mood disorders, co- activation -> heightened infections) vascular disease Adapted from slide courtesy of Serena Spudich Spudich et al. J Infect Dis 2011, Valcour et al. J Infect Dis 2012 Resulting in CNS inflammation, immune CNS injury persists despite initiation of activation and morphologic changes ART and virologic suppression Elevated CSF markers of macrophage and lymphocyte activation present in primary HIV infection (median 2.5 months from infection) and reduced putaminal Even after achieving virologic suppression on ART, markers of immune brain volumes (median 3.33 months from activation and inflammation are persistently elevated compared with infection) uninfected controls Spudich et al. J Infect Dis 2011, Wright et al. AIDS 2016 Price et al. J Neuroimmune Pharmacol 2013 2
12/7/17 But may not be adequate to prevent Initiation of ART early in infection may mitigate inflammatory changes in the CNS cognitive impairment *Cognitive performance *Evidence of improved across the board after initiation progressive of ART in acute inflammation and infection, but only improvement in 1 gliosis present by test was significantly MRS early in greater than infection but controls attenuated after *Of 8 participants initiation of ART with evidence of cognitive impairment at baseline, none improved after initiating ART Young et al. Neurology 2014 Kore et al. JAIDS 2015 The majority of persons living with HIV in Aging HIV population at greater risk of the US are >50 years of age cognitive impairment After adjusting for expected effects of age using normative controls and other variables, odds of cognitive impairment increased by 20% per decade of advancing age http://www.positivelite.com/index.php/item/the-growing-invisible-majority-and-what-do-people-aging-with-hiv-really- need, https://www.cdc.gov/hiv/group/age/olderamericans/index.html Coban et al. AIDS 2017 3
12/7/17 And cerebrovascular disease Neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s) In ALLRT cohort , rates of stroke higher with each decade of advancing age. years No. of strokes 54 3 17 20 14 Chow et al. CROI 2016, Person-years 32,023 12,780 11,396 5,954 1,893 manuscript Rate (per 1000 PY) 1.69 0.23 1.49 3.36 7.39 Makitalo et al. AIDS Res Ther 2015, Turner et al. Alzheimers Dement 2016 under review Cerebrovascular risk factors are associated Greater burden of cerebral white matter disease with worse cognitive function in HIV associated with worse cognitive function Per 10 mg/dL higher HDL In Multicenter AIDS cohort , higher cholesterol and lower HDL associated with increased rate of *ART-treated PLWH have greater burden of cerebrovascular disease compared longitudinal with HIV-uninfected counterparts, which correlated with cognitive impairment cognitive decline * White matter hyperintensities mediate Odds ratio association In HAILO cohort , HDL >60 mg/dL ê between HIV and odds of cognitive impairment by 45% cognitive impairment (p=0.004) Makanjuola et al. IAS 2017, Mukerji et al. Clin Infect Dis 2016 Watson et al. J Neurovirol 2017, Su et al. AIDS 2016 4
12/7/17 Penetration of ARVs into CNS is highly variable Clinical case: He has been doing well on TDF/FTC/EVG/COBI for the past few years with excellent adherence. Would you recommend changing his ARVs to a regimen with better CNS penetration? Dolutegravi Elvitegravir r Adapted from Letendre Top Antivir Med 2011 Better CNS penetration associated with The relationship between CNS penetration and virologic suppression in the CSF cognitive impairment remains unclear *CPE score lower among those with detectable virus in the p=0.011* CSF p=0.032* * Higher CNS penetration score correlated with lower prevalence of cognitve impairment Carvalhal et al. J Neurovirol 2015 Marra et al. AIDS 2009, Cusini et al. JAIDS 2013 5
12/7/17 RCT of CNS-targeted ARVs demonstrated The relationship between CNS penetration and cognitive impairment remains unclear no significant benefit in cognitive function • High CPE score (vs. low CPE score) associated with 75% higher hazard of HIV dementia (aHR 1.74, 95% CI 1.15- 2.65) *No significant improvement in global deficit score (lower values indicate improving performance) after 16 weeks among those who received CNS-targeted therapy Marra et al. AIDS 2009, Caniglia et al. Neurology 2014 Ellis et al. Clin Infect Dis 2014 Neurotoxicity of ARVs may also impact T olerability, potency, and efficacy remain key considerations when selecting ART for persons with cognitive impairment cognitive function • RAL CSF concentrations exceed 50% RAL *Neuropsychiatric inhibitory concentrations in all AEs (e.g., headache, TDF- EVG/c insomnia, • No EVG CSF pharmacokinetic data* FTC depression/anxiety) • DTG CSF concentrations exceed 50% reported with DTG use inhibitory concentrations in all (~2-10%), significantly • Fewer CNS side effects than EFV DTG higher than RAL and ABC-3TC • No ABC CSF pharmacokinetic data on daily EVG use (1-2%) dosing *DTG + ABC, DTG in Removed • EFV short- and long-term neurotoxicity; women, and DTG in EFV can exacerbate psychiatric symptoms older age associated • ATV CSF concentrations do not consistently with more than twice DRV/r ATV/r exceed inhibitory concentrations the risk of • Associated with CSF viral escape neuropsychiatric AEs • RPV CSF concentrations do not consistently RPV exceed inhibitory concentrations Slide courtesy of Scott Letendre, Last updated 17 Oct 2017; Available at http://www.aidsinfo.nih.gov/guidelines De Boer et al. AIDS 2016, Hoffmann et al. HIV Med 2016, Elzi et al. AIDS 2017, Penafiel et al. J Antimicrob Chemother 2017 6
12/7/17 Most treatment trials for cognitive function in HIV have not demonstrated clear benefit Clinical case: His ARV regimen was • Anti-inflammatory & antioxidant agents changed to ABC/3TC/DTG about 6 • Selegiline (Schifitto et al. Neurology 2009) • Minocycline (Nakasujja et al. Neurology 2013, Sacktor et al. J Neurovirol 2013) months ago, and he is tolerating this • Statins (Erlandson et al. Clin Infect Dis 2017, observational) regimen well. His memory impairment is • Treatment intensification stable but not improved. Are there other • Raltegravir (Dahl et al. J Infect Dis 2011) adjunctive therapies to consider? • Other • Memantine, NMDA antagonist (Zhao et al. HIV Clin Trials 2010) • Nimodipine (Navia et al. Neurology 1998) Benefit of treatment Benefit of treatment intensification during intensification on global acute HIV on cognitive function cognitive function n=30 Moderate to large effect of n=32 maraviroc intensification *Initiation of ART observed at 6 and 12 mos + RAL + MVC on global cognitive function during acute HIV associated with 24-week better cognitive cenicriviroc performance at 24 intensification weeks but not improved significantly global different than non- cognitive intensified function, treatment arm working memory and attention Valcour et al. PLOS One 2015 Gates et al. AIDS 2016, Ndhlovu et al. CROI 2017 7
12/7/17 Paroxetine associated with improved cognitive function Physical in a randomized, double-blind, placebo-controlled trial activity associated with better brain integrity * Executive function but not motor function better in physically active individuals compared with sedentary *Physically active individuals have larger putaminal volumes compared with sedentary individuals across the age *Participants randomized to paroxetine performed better on most span neuropsych testing at Week 24 Sacktor et al. J Neurovirol 2017 Ortega et al. J Int Neuropsychol Soc 2015 Considerations in persons living with HIV Short aerobic exercise program intervention did not improve cognitive function with cognitive impairment *At baseline, physical • Optimize ARV regimen activity and aerobic fitness associated with • Minimize polypharmacy better cognitive performance. • Address psychiatric comorbidities (e.g., depression, substance use) *No change in cognitive • Aggressive vascular risk factor modification: the earlier, the better performance after 16- week aerobic exercise • Screen for and treat other comorbidities (e.g., sleep apnea, program (60% hepatitis C) adherence) • Encourage physical, mental, social activity Mcdermott et al. AIDS Care 2017 8
Recommend
More recommend
