CAB 59: HIV and neurocogni5ve impairment

Transcription

1 HIV Neurology CAB 59: HIV and neurocogni5ve impairment Friday 8 th July 2016 Dr Nick Davies Consultant Neurologist, Chelsea & Westminster Hospital & Imperial College NHS Trust (Charing Cross Hospital), London

2 Aims of talk Pre-ART Neurology Post-ART IRIS Cogni<ve Impairment: HAND; drug toxicity Major omissions Peripheral Neuropathy Stroke (Myles Connor)

3 Introduc<on What is the Human Immunodeficiency Virus? Retrovirus (ssrna); possesses reverse transcriptase Infects: CD4 T helper cells Macrophages Dendri<c cells Microglia Lymphotropic & Neurotropic M-tropic (CCR5); T-tropic (CXCR4) HIV-1 & HIV-2 HIV-1 clades (A to E) B commonest US & Europe

4 Neurological Complica<ons of Immunosuppression Davies, N. & Thwaites, G. Infections of the nervous system. Pract Neurol 11, (2011).

5 An<-retroviral Therapy Source: Yin et al. HIV in the UK 2014 Report: data to end of Nov 2014; PHE, London

6 Sites of Action of Current Antiretroviral Drug Classes Source of image:

7 Immune Recons<tu<on Inflammatory Syndrome (IRIS) Definition: a paradoxical deterioration in clinical status attributable to the recovery of the immune system during HAART. Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, (2010).

8 IRIS: Classifica<on 1 1 Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, (2010).

9 IRIS: Classifica<on 1 Simultaneous = Unmasked Delayed = Paradoxical Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, (2010).

10 14/8/15 04/9/15

11 14/8/15 04/9/15 06/10/15

12 IRIS: Classifica<on 1 CD8 Encephalitis 2 With HIVE Without HIVE Autoimmune Conditions: GBS SLE Grave s disease 1 Johnson, T. & Nath, A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 1184, (2010). 2 Miller, R.F., Isaacson, P.G., Hall-Craggs, M., et al. Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART. Acta Neuropathol 108, (2004).

13 HIV Cogni<ve Impairment pre-cart HIV demen<a; HIV encephalopathy; AIDS demen<a complex Life<me prevalence 15% 30% terminal AIDS Subcor<cal demen<a triad: CogniHon; Motor funchon; Behaviour Navia et al (Price) The AIDS Dementia Complex Annals of Neurology 19: McArthur, J.C., Brew, B.J. & Nath, A. Neurological complications of HIV infection. Lancet Neurol. 4, (2005). Manji (2013) HIV, Dementia, & ARVs: 30 years of an epidemic JNNP 84:

14 HIV Cogni<ve Impairment: Arrival of ART HIV Demen<a now only seen because: Burnt-out damage sustained prior to ART Late presentahon Non-adherence to ARVs Rarely in pa<ents where CNS & systemic infec<on follow non-parallel courses Long-term non-progressors On ART; different resistance pa`erns Compartment phenomenon SymptomaHc CSF escape» Can be fulminant with seizures Schouten, J., Cinque, P., Gisslen, M., Reiss, P. & Portegies, P. HIV-1 infection and cognitive impairment in the cart era: a review. AIDS 25, (2011).

15 HIV Cogni<ve Impairment: cart-era Pa<ents with systemic control of HIV and high CD4 cell counts complaining of: Mild memory problems Slowness DifficulHes in concentrahon DifficulHes in planning DifficulHes in mulhtasking Pa<ents with neurodegenera<ve disease ARVs Schouten, J., Cinque, P., Gisslen, M., Reiss, P. & Portegies, P. HIV-1 infection and cognitive impairment in the cart era: a review. AIDS 25, (2011).

16 A new terminology: HAND Frascati Criteria 1 Nb If criterion has Normal distribution 2.3% fall >2SD; 15.9% >1 SD 2 1 Antinori, A., et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69, (2007). 2 Gisslen, M., Price, R.W. & Nilsson, S. The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence? BMC Infect Dis 11, 356 (2011).

17 HIV Cogni<ve Impairment: ART-era CHARTER study (CNS HIV ARV Therapy Effects Research) 52% Cogni<ve impairment (n=1555) 33% Asymptoma<c Neurocog Impairment 12% Mild Neurocog Disorder 2% HAD Higher incidence CI in those with more comorbi<es 40%; 59%; 83% Heaton, R.K., et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75, (2010).

18 HIV Cogni<ve Impairment: cart-era What about confounds? 1 Current drug use Hepa<<s C co-infec<on Depression Burnt out CNS disease HAND incidence Virologically suppressed: 18% Non-virologically suppressed: 24% UK study in suppressed asymptoma<c: 19% 2 STUDIES TYPICALLY CROSSECTIONAL NOT LONGITUDINAL 1 Cysique, L.A. & Brew, B.J. Prevalence of non-confounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression. J Neurovirol 17, (2011). 2 Garvey, L., Surendrakumar, V. & Winston, A. Low Rates of Neurocognitive Impairment Are Observed in Neuro-Asymptomatic HIV-Infected Subjects on Effective Antiretroviral Therapy. HIV Clin Trials 12, (2011).

19 Summary of Revised (2010) CNS Penetra<on- Effec<veness (CPE) Ranking of ARVs NRTIs AZT ABC ddi TDF FTC 3TC ddi d4t NNRTIs NVP DLV ETV EVF PIs IDV/r DRV/r ATV/r NFV FPV/r ATV RTV IDV FPV SQV/r LPV/r SQV Fusion/Entry Inhibitors Integrase inhibitors MVC RAL ENF Letendre, S et al. 17 th CROI Abstract 430.

20 HIV Cogni<ve Impairment: cart-era CPE Evidence: Smurzynski et al Cross-sec<onal study; VL<50 Higher CPE score in those on >3 ARVs be`er than lower CPE score Marra et al Dichotomised CPE (old) >2 or <2 Higher CPE associated with greater CSF suppression Those with impaired neuropsych at entry did worse with higher CPE 1 Smurzynski et al Effects of CNS ARV penetration of cognitive in ALLRT AIDS 2011; 25: Marra, C.M., et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 23, (2009)

21 HIV Cogni<ve Impairment: cart-era Problems with CPE: Categorical not ordinal Methodology not transparent: Hard to independently validate Weighting for each criterion? ARV-ARV interactions not considered No accounting for the effect of an impaired BBB Anatomy: CSF not a liquid brain biopsy Efficacy in brain cells not assessed specifically Toxicity (CNS/CVS) not considered Slide from Dr Anton Pozniak; Consultant Physician, C&W.

22 HIV Cogni<ve Impairment: cart-era Randomised control trial high CPE vs low CPE No neuropsychological benefit at 16 weeks Higher detectable plasma HIV viral load in high CPE group (i.e. treatment failure) Ellis RJ, Letendre S, Vaida F, Haubrich R, Heaton RK, Sacktor N, Clifford DB, Best BM, May S, Umlauf A, Cherner M, Sanders C, Ballard C, Simpson DM, Jay C, McCutchan JA. Randomized Trial of Central Nervous System-Targeted Antiretrovirals for HIV-Associated Neurocognitive Disorder. Clin Infect Dis Jan 14.

23 HIV Cogni<ve Impairment: Toxicity ACTG 5170 Mul<centre study of discon<nua<on of ARVs in those with CD4 >350 Mixture of ARVs Robertson, K.R., et al. Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 74, (2010). Winston, A., et al. Dynamics of cognitive change in HIV-infected individuals commencing three different initial antiretroviral regimens: a randomized, controlled study. HIV Med (2011). EFAVIRENZ

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25 An Approach to Assessment & Treatment of Cognitive Impairment in ART-treated HIV patients. From: Davies & Brew (2014) Clinical Aspects of HIV-Related Neurocognitive Disorders In: HIV & Psychiatry, Editors: Joska, Stein & Grant. DOI: / ch3

26 HIV Cogni<ve Impairment: cart-era What will be the effect of long-term ARV exposure to the CNS? Mitochondria; proteosomes What will be the effect of vascular dysfunc<on? What will be the effect of dyslipidaemia?