Serena S. Spudich, MD Professor of Neurology Yale University New Haven, Connecticut

Transcription

1 HIV Reservoirs in the Brain: Where, When, How, and What Do They Mean for Our Patients? Serena S. Spudich, MD Professor of Neurology Yale University New Haven, Connecticut FORMATTED: // Financial Relationships With Commercial Entities Dr. Spudich has no relationships with commercial entities. (Updated //) Slide of Learning Objectives After attending this presentation, learners will be able to: Describe how HIV reservoirs are established in the brain. Monitor for CSF escape in patients with neurological symptoms and treated HIV. Describe possible effects of HIV cure strategies on the brain. Slide of

2 A patient on cart has a new onset difficulty with walking and stammering speech. A brain MRI is normal. You tell him that the first step in his management should be: Slide of %. To increase the CNS penetration of his antiretroviral regimen. %. Comprehensive neuropsychological testing. %. Treatment regimen switch given concern for cart side effects. %. Lumbar puncture for cerebrospinal fluid testing. %. Physical therapy for gait training. Berlin patient revealed possibility of HIV cure, creating new critical question is the brain an HIV reservoir? Slide of Doing well off ART > 8 years No replication competent HIV Waning HIV antibodies No HIV specific T cells Slide courtesy of Steve Deeks Key questions relevant to brain reservoirs for HIV Slide of Do HIV reservoirs exist in the brain during cart? How should we optimize brain health in our patients? How/when are HIV reservoirs established in the brain? How will HIV cure strategies impact the brain?

3 Thuso: year old man with difficulty walking Slide of yo man presented / with leg weakness and balance difficulty, vague cognitive symptoms, + urinary incontinence. Diagnosed with HIV in 8, cart naïve. Labs: Plasma HIV RNA. million cps/ml and CD cells/ul. CSF microbiology all negative, except CSF HIV RNA > million cps/ml. MRI Brain (FLAIR sequence) shown below with atrophy and diffuse subcortical white matter changes. Slide 8 of Thuso: year old man with difficulty walking HIV RNA(lo Diagnosis: HIV associated dementia. QNZP Since the beginning of the epidemic, CNS involvement has been a hallmark of HIV. In some individuals, HIV particularly manifests as CNS dysfunction with profound CNS HIV replication. Days post ART initiation Do reservoirs for HIV exist within the brain in most asymptomatic patients? Digit Symbol (DSY) -8 - QNPZ summarized neurologic DSY performance Days Mechanisms of CNS HIV infection prior to ART Brain Neurotoxic products (free radicals, cytokines) Slide 9 of HIV proteins (gp, tat) Neopterin Chemokines (IP, MCP ) Blood brain barrier breakdown Blood HIV tat

4 Key questions relevant to brain reservoirs for HIV Slide of Do HIV reservoirs exist in the brain during cart? How should we optimize brain health in our patients? How/when are HIV reservoirs established in the brain? How will HIV cure strategies impact the brain? Persistent macrophage/microglial activation on cart with plasma viral suppression / HIV Slide of Positron emission tomography (PET): Abnormal brain uptake of ligand specific for activated microglial cells (> years of ART vs HIV ). Brain autopsy: Increased activated microglia (CD8+ cells) in (>. years ART vs HIV ). CSF: Elevated CSF neopterin, marker of macrophage activation, associates with detectable CSF HIV RNA by single copy assay (> years of ART). Garvey et al, AIDS. ; Anthony et al, J Neuropath Exp Neur, ; Dahl et al, AIDS. HIV DNA detected in brain on ART with plasma viral suppression (sudden death) Slide of HIV RNA seldom measurable in brain Slide and data courtesy of Joe Wong Wong, Yukl, et al, Keystone HIV Persistence Conference, April

5 Persistent CNS HIV replication on ART with plasma viral suppression: CNS escape Slide of Lamivudine Abacavir Lopinavir/r hand tremor, ataxia, slurred speech, aphasia Latest CD 8 cells/ul; nadir CD cells/ul Peluso et al., AIDS,. Persistent CNS HIV replication on ART with plasma viral suppression: CNS escape Slide of CSF HIV RNA CSF WBC = cells/ul Peluso et al., AIDS,. Persistent CNS HIV replication on ART with plasma viral suppression: CNS escape PI: IV, KR, MI, IV, LP, V8A RT: ML, ED, DN, V8I, M8V, LW, TY Abacavir Lamivudine Darunavir/r Nevirapine Zidovudine Resolution of signs and symptoms Zidovudine Didanosine Lamivudine Stavudine Abacavir Tenofovir Nevirapine Delavirdine Efavirenz Saquinavir Indinavir Ritonavir Nelfinavir Amprenavir Lopinavir/r Atazanavir Possible Possible Slide of No Evidence of No Evidence of No Evidence of Possible Possible Peluso et al., AIDS,.

6 Log Log HIV HIV viral viral load load (RNA (RNA copies/ cp/ml) THINC Subject : CSF escape at two time intervals Pre- HAART T T St ar t ed DRV/ r/ TDF/ FTC years after diagnosis Blood plasma CSF Months on HAART Slide of Persistent CNS HIV replication on ART with plasma viral suppression: CNS escape Perc ent Infectivity at Low CD Elevated macrophage tropism of CSF escape population Ba L JRCSF D E9 F A UNC Joseph et al., THINC study Jake: Young man with recent infection, hesitant to start ART 9 yo man diagnosed in May,, probable acute HIV syndrome in Oct. On no meds, works as an electrical engineer; lives alone and has good support network. He wants to avoid treatment as long as possible. / / 9/ CD count 8 CD % HIV RNA 9 Slide of Key questions relevant to brain reservoirs for HIV Slide 8 of Do HIV reservoirs exist in the brain during cart? How should we optimize brain health in our patients? How/when are HIV reservoirs established in the brain? How will HIV cure strategies impact the brain?

7 HIV traffics into the CNS in early infection Slide 9 of 8 HIV RNA Levels Plasma log copies/ml 9 8 Days Post HIV Transmission HIV traffics into the CNS in early infection Slide of 8 HIV RNA Levels Plasma CSF log copies/ml 9 8 Days Post HIV Transmission HIV traffics into the CNS in early infection Slide of 8 HIV RNA Levels CSF log copies/ml 9 8 Days Post HIV Transmission

8 CSF Neopterin Slide of Macrophage activation in the CNS is triggered in early infection 8 nmol/l 9 8 Days Post HIV Transmission Neopterin, biomarker of macrophage activation, is elevated in the CNS compared to HIV negative (dotted line) throughout early infection. Neuronal injury begins during early infection Slide of CSF NFL ng/l HIV- Acute AHI Primary PHI Chronic CHI HIV HIV HIV Neurofilament Light Chain (NFL) specific CSF biomarker of axonal injury Peluso et al., JID Slide of 8 HIV RNA Levels CSF log copies/ml 9 8 Days Post HIV Transmission 8

9 Local CNS HIV replication can be established during early infection Slide of Compartmentalized evolution of CSF HIV beginning ~ months post infection TMRCA time to most recent common ancestor Sturdevant C., PloS Pathogens Key questions relevant to brain reservoirs for HIV Slide of Do HIV reservoirs exist in the brain during cart? How should we optimize brain health in our patients? How/when are HIV reservoirs established in the brain? How will HIV cure strategies impact the brain? How will HIV cure strategies affect the CNS? ART cure intervention ART Interruption ART Slide of Pre ART On ART During intervention/ before ATI At plasma rebound (or before) On ART in follow up protocol CSF: inflammatory markers, virology, injury markers Neuroimaging: MRS, volumetrics, DTI & rs fmri at Tesla magnet strength Clinical: Neurological exams & neuropsychological assessments Collaborators: V. Valcour, J. Ananworanich 9

10 SEARCH : HIV cure intervention with HDAC inhibitor, followed by treatment interruption HIV RNA (cps/ml) A. Plasma HIV RNA Baseline Wk VHM ATI On ART HIV RNA (cps/ml) C. CSF HIV RNA Single Copy Assay Baseline Wk VHM ATI Slide 8 of A. CSF Protein B. CSF IP-/CXCL p =. Protein (mg/dl) IP-/CXCL (pg/ml) Baseline Wk VHM ATI Baseline Wk VHM ATI VHM: Vorinostat (HDAC inhibitor) + Hydroxychloroquine + Maraviroc Kroon, et al., IAS Cure Symposium & IAS, Key questions relevant to brain reservoirs for HIV Slide 9 of Do HIV reservoirs exist in the brain during cart? How should? we optimize brain health in our patients? How/when are HIV reservoirs established in the brain? How will HIV cure strategies impact the brain? Start cart treatment early CSF Neuronal Injury Marker (NFL) Post ART Trailmaking A Post ART in Acute HIV Slide of After months of cart started in acute HIV (Thailand): No CSF signs of neuronal injury. Preserved normal cognitive test performance. Normal cognitive performance in individuals starting ART within months of infection (USA). Peluso et al.,jid; Kore JAIDS ; Evering et al., AIDS.

11 Encourage cart adherence CSF HIV rebound accompanied by marked CNS inflammation after ART interruption HIV RNA (log cps/ml) HIV RNA (log cps/ml) Plasma HIV RNA Slide of 8 CSF HIV RNA 8 CSF WBCs cells/ L Price, Deeks, J Neurovirology. 8 Days Investigate whether CNS cart exposure matters Impact of higher CNS Penetration Effectiveness (CPE) regimens Lower CSF viral load (Letendre CROI, Marra AIDS 9) Worsened neuropsychological performance (Marra AIDS, 9). Better neuropsychological improvement in impaired subjects (Tozzi J AIDS, 9; Smurzynski AIDS, ). Slide of Monotherapy or dual therapy increased risk of CSF escape? (Ferretti Seminars Neurol ) Potential neurotoxicity of ART: efavirenz (Leutscher Scand J Infect Dis ; Ciccarelli Neurology ),? Integrase inhibitors? Slide of Investigate whether CNS cart exposure matters ACTG A: Effects of ART intensification on the brain Randomized, placebo controlled, double blinded phase IV clinical trial, 9 weeks Study Population (n=8; arms=) Mild neurocognitive impairment (includes neuroasymptomatic) On stable ART treatment > year Plasma HIV RNA less than copies/ml Study Regimens A: No intensification B: Intensification with DTG C: Intensification with DTG and MVC Weill Cornell Uptown Site E 8 th St at York Avenue Valery Hughes, FNP 9 Weill Cornell Chelsea Site W rd St between th and th Todd Stroberg, RN 98 New Jersey Medical Center Site Bergen Street, Newark Susana Rivera BSN, RNC 9 9 9

12 Clinical guidelines for HIV and the brain in Slide of USA HIV treatment guidelines ( Treat all individuals at the time of HIV diagnosis. HIV guidelines now incorporate CNS considerations: Due to CNS toxicities, efavirenz no longer in first line recommended regimens. Treatment recommendations for HIV Associated Dementia (no efavirenz, favor regimens with higher presumed CNS penetration). Evaluation/treatment of symptomatic CNS escape including lumbar puncture for CSF viral load, CSF drug resistance testing and consideration of CNS penetration. Acknowledgements Yale: Michael Kozal Brinda Emu Leah Le Jen Chiarella Barbara Turcotte Laurie Andrews Sebastian Urday Michael Peluso Andrew Young Joome Suh Idil Kore Elham Rahimy Andrew Silverman Tess O Meara UCSF/San Francisco: Victor Valcour Joanna Hellmuth Collin Adams Lauren Wendelken Richard W. Price Evelyn Lee Julia Peterson Rick Hecht Chris Pilcher UCSF Options Study Magnet Staff Teri Liegler Study Participants UNC: Ron Swanstrom Sarah Joseph Christa Sturdevant Gretja Schnell Kevin Robertson Joe Eron THINC team Sydney: Bruce Brew Sarah Palmer Innsbruck: Dietmar Fuchs WRAIR/MHRP Jintanat Ananworanich Sodsai Tovanabutra Gustavo Kijak Suteeraporn Pinyakorn Nelson Michael Jerome Kim Merlin Robb U. Gothenburg: Lars Hagberg Magnus Gisslen Funding Support Henrik Zetterberg Milan: Paola Cinque NIH RMH RMH9999 RMH8 RMH9 R NS89 KMH W8XWH ; IAA number NIAID Y AI US Military HIV Research Program Slide of Study Participants Thai Red Cross AIDS Res Center/SEARCH Nittaya Phanuphak Praphan Phanuphak Mark de Souza Frits van Griensven James Fletcher Eugene Kroon Donn Colby Carlo Nitiya Chomchey Duanghathai Suttichom Somprartthana Rattanamanee Peeraya Mungu Putthachard Saengtawan Tippawan Pankam A patient on cart has a new onset difficulty with walking and stammering speech. A brain MRI is normal. You tell him that the first step in his management should be: Slide of %. To increase the CNS penetration of his antiretroviral regimen. %. Comprehensive neuropsychological testing. %. Treatment regimen switch given concern for cart side effects. 8%. Lumbar puncture for cerebrospinal fluid testing. %. Physical therapy for gait training.

13 Slide of A patient on cart has a new onset difficulty with walking and stammering speech. A brain MRI is normal. You tell him that the first step in his management should be: To increase the CNS penetration of his antiretroviral regimen. Treatment regimen switch given concern for cart side effects. % % % % % % % 8% Physical therapy for gait training. % % First Slide Second Slide HIV Reservoirs in the Brain: Where, When, How, and What Do They Mean for Our Patients? Serena S. Spudich, MD Professor of Neurology Yale University New Haven, Connecticut FORMATTED: //