The document summarizes a presentation on neurocognitive complications of HIV disease. The presentation was given at the UC San Diego AntiViral Research Center, which sponsors weekly presentations on infectious diseases research. The goal is to provide current research, clinical practices, and trends in diseases like HIV, HBV, HCV, and TB. The slides from this particular presentation on neurocognitive complications of HIV are intended for educational purposes of the audience and may not be used for other purposes without permission.
Richard Haubrich, M.D., and David Wyles, M.D. of UC San Diego Antiviral Research Center, presents "Update from the American Association for the Study of Liver Diseases Meeting" at AIDS Clinical Rounds
David L. Wyles, M.D., of UCSD, presents "On again, off again... on again? Resistance testing for the management of HCV infection" at AIDS Clinical Rounds
Richard Haubrich, M.D., and David Wyles, M.D. of UC San Diego Antiviral Research Center, presents "Update from the American Association for the Study of Liver Diseases Meeting" at AIDS Clinical Rounds
David L. Wyles, M.D., of UCSD, presents "On again, off again... on again? Resistance testing for the management of HCV infection" at AIDS Clinical Rounds
Wesley Campbell, M.D., of U.S. Navy Medicine, presents "Neurocognitive Changes in Newly Diagnosed Patient with Low CD4: Implications for Prognosis and Employment"
The views expressed in the presentations are that of the author and do not necessarily reflect the views of the Government of Canada. Presentations are shared in the original format received from the presenter.
Presentations given at the Conference to Develop a Federal Framework on Lyme Disease are the property of the author, unless otherwise cited. If you reference the author's work, you must give the author credit by naming the author and their work as well as the place and date it was presented.
For more information, contact the Lyme Disease Conference Secretariat at maladie_lyme_disease@phac-aspc.gc.ca
High Sensitivity HIV Testing and Translational Science around PrEPHopkinsCFAR
Joanne Stekler, MD MPH
Associate Professor, Department of Medicine
University of Washington
Inter-Center for AIDS ResearchAntiretroviralsfor Prevention Working Group
November 13, 2017
Phillip Keen (Kirby Institute) discusses the successes and challenges of community-based HIV testing.
This presentation was given at the AFAO National HIV Forum, 17 October 2014.
Топ достижений лечения ВИЧ в 2017 г / Top Advances in ART for 2017hivlifeinfo
Top Advances in ART for 2017
In this downloadable slideset, Joel E. Gallant, MD, MPH, provides a comprehensive update on ART management.
Format: Microsoft PowerPoint (.ppt)
File size: 579 KB
Date posted: 3/29/2017
David Moore, PhD, of UC San Diego HIV Neurobehavioral Research Program, presents "Understanding and Evaluating the Neuropsychological Functioning of HIV-infected Persons"
Современное лечение ВИЧ: лечение ВИЧ у пациентов с вирусными гепатитами.Conte...hivlifeinfo
Современное лечение ВИЧ: лечение ВИЧ у пациентов с вирусными гепатитами.Contemporary Management of HIV. Managing HIV in Viral Hepatitis Coinfection.2016
In this downloadable slideset, David L. Wyles, MD, and Program Director Eric S. Daar, MD, review key data and optimal approaches for ART management in patients with HIV and viral hepatitis coinfection.
Format: Microsoft PowerPoint (.ppt)
File size: 1.85 MB
Современное лечение ВИЧ : лечение возрастных пациентов.2017/Contemporary Management of HIV. Management of Aging Patients.2017
In this downloadable slideset, Edgar Turner Overton, MD, and Program Director Joseph J. Eron, Jr., MD, review key data on managing aging patients with HIV.
Source: Contemporary Management of HIV
Date Posted: 4/24/2017
Современное лечение ВИЧ: АРТ у пациентов с сопутствующими заболеваниями.Conte...hivlifeinfo
Современное лечение ВИЧ:АРТ у пациентов с сопутствующими заболеваниями.//Contemporary Management of HIV. Managing ART in HIV-Infected Patients With Common Comorbidities. 2016
In this downloadable slideset, David A. Wohl, MD, and Program Director Eric S. Daar, MD, review key data and optimal approaches for managing ART in the context of common comorbidities.
Format: Microsoft PowerPoint (.ppt)
File size: 3.51 MB
Современное лечение ВИЧ : АРТ как профилактика.Contemporary Management of HIV...hivlifeinfo
Contemporary Management of HIV. Antiretroviral Therapy As Prevention.2016
In this downloadable slideset, Kenneth Mayer, MD, and Program Director Eric S. Daar, MD, review key data and optimal approaches for pre- and post-exposure prophylaxis in patients at risk for HIV infection.
Format: Microsoft PowerPoint (.ppt)
File size: 2.13 MB
Современное лечение ВИЧ: новые подходы к оптимизации АРТ/Contemporary Managem...hivlifeinfo
Вопросы, связанные с АРТ первого ряда, смена арв-стратегии для пациентов с вирусной супрессией, акцентом на возрастающую роль новыхантиретровирусных стратегий.
Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy- E...Hivlife Info
In this downloadable slideset, Joseph J. Eron, Jr., MD, and Daniel Kuritzkes, MD, review key data on the evolving use of INSTIs in patients beginning HIV therapy.
Format: Microsoft PowerPoint (.ppt)
File size: 2.29 MB
This presentation focusses on the importance of diagnostic biomarkers for Alzheimer's disease. MRI, amyloid PET and CSF biomarkers are discussed in detail.
Wesley Campbell, M.D., of U.S. Navy Medicine, presents "Neurocognitive Changes in Newly Diagnosed Patient with Low CD4: Implications for Prognosis and Employment"
The views expressed in the presentations are that of the author and do not necessarily reflect the views of the Government of Canada. Presentations are shared in the original format received from the presenter.
Presentations given at the Conference to Develop a Federal Framework on Lyme Disease are the property of the author, unless otherwise cited. If you reference the author's work, you must give the author credit by naming the author and their work as well as the place and date it was presented.
For more information, contact the Lyme Disease Conference Secretariat at maladie_lyme_disease@phac-aspc.gc.ca
High Sensitivity HIV Testing and Translational Science around PrEPHopkinsCFAR
Joanne Stekler, MD MPH
Associate Professor, Department of Medicine
University of Washington
Inter-Center for AIDS ResearchAntiretroviralsfor Prevention Working Group
November 13, 2017
Phillip Keen (Kirby Institute) discusses the successes and challenges of community-based HIV testing.
This presentation was given at the AFAO National HIV Forum, 17 October 2014.
Топ достижений лечения ВИЧ в 2017 г / Top Advances in ART for 2017hivlifeinfo
Top Advances in ART for 2017
In this downloadable slideset, Joel E. Gallant, MD, MPH, provides a comprehensive update on ART management.
Format: Microsoft PowerPoint (.ppt)
File size: 579 KB
Date posted: 3/29/2017
David Moore, PhD, of UC San Diego HIV Neurobehavioral Research Program, presents "Understanding and Evaluating the Neuropsychological Functioning of HIV-infected Persons"
Современное лечение ВИЧ: лечение ВИЧ у пациентов с вирусными гепатитами.Conte...hivlifeinfo
Современное лечение ВИЧ: лечение ВИЧ у пациентов с вирусными гепатитами.Contemporary Management of HIV. Managing HIV in Viral Hepatitis Coinfection.2016
In this downloadable slideset, David L. Wyles, MD, and Program Director Eric S. Daar, MD, review key data and optimal approaches for ART management in patients with HIV and viral hepatitis coinfection.
Format: Microsoft PowerPoint (.ppt)
File size: 1.85 MB
Современное лечение ВИЧ : лечение возрастных пациентов.2017/Contemporary Management of HIV. Management of Aging Patients.2017
In this downloadable slideset, Edgar Turner Overton, MD, and Program Director Joseph J. Eron, Jr., MD, review key data on managing aging patients with HIV.
Source: Contemporary Management of HIV
Date Posted: 4/24/2017
Современное лечение ВИЧ: АРТ у пациентов с сопутствующими заболеваниями.Conte...hivlifeinfo
Современное лечение ВИЧ:АРТ у пациентов с сопутствующими заболеваниями.//Contemporary Management of HIV. Managing ART in HIV-Infected Patients With Common Comorbidities. 2016
In this downloadable slideset, David A. Wohl, MD, and Program Director Eric S. Daar, MD, review key data and optimal approaches for managing ART in the context of common comorbidities.
Format: Microsoft PowerPoint (.ppt)
File size: 3.51 MB
Современное лечение ВИЧ : АРТ как профилактика.Contemporary Management of HIV...hivlifeinfo
Contemporary Management of HIV. Antiretroviral Therapy As Prevention.2016
In this downloadable slideset, Kenneth Mayer, MD, and Program Director Eric S. Daar, MD, review key data and optimal approaches for pre- and post-exposure prophylaxis in patients at risk for HIV infection.
Format: Microsoft PowerPoint (.ppt)
File size: 2.13 MB
Современное лечение ВИЧ: новые подходы к оптимизации АРТ/Contemporary Managem...hivlifeinfo
Вопросы, связанные с АРТ первого ряда, смена арв-стратегии для пациентов с вирусной супрессией, акцентом на возрастающую роль новыхантиретровирусных стратегий.
Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy- E...Hivlife Info
In this downloadable slideset, Joseph J. Eron, Jr., MD, and Daniel Kuritzkes, MD, review key data on the evolving use of INSTIs in patients beginning HIV therapy.
Format: Microsoft PowerPoint (.ppt)
File size: 2.29 MB
This presentation focusses on the importance of diagnostic biomarkers for Alzheimer's disease. MRI, amyloid PET and CSF biomarkers are discussed in detail.
How health analytics are changing the way we understand and manage healthcare. Presented by Professor Enrico Coiera, Faculty of Medicine at the University of NSW, Australia, at HINZ 2014, 11 November 2014, 10am, Plenary Room
Project ECHO (Extension for Community Health Outcomes)icornpresentations
Sanjeev Arora MD, Distinguished Professor of Medicine (Gastroenterology/Hepatology); Director of Project ECHO®
Department of Medicine, University of New Mexico Health Sciences Center
Published Research, Flawed, Misleading, Nefarious - Use of Reporting Guidelin...John Hoey
Much published health sciences literature is misleading and biased
Efforts to correct this include use of reporting guidelines- criteria for doing science and reporting the results properly
Also discussion of conflicts of interest - how to report them.
Using real-world evidence to investigate clinical research questionsKarin Verspoor
Adoption of electronic health records to document extensive clinical information brings with it the opportunity to utilise that information to support clinical research, and ultimately to support clinical decision making. In this talk, I discuss both these opportunities and the challenges that we face when working with real-world clinical data, and introduce some of the strategies that we are adopting to make this data more usable, and to extract more value from it. I specifically discuss the use of natural language processing to transform clinical documentation into structured data for this purpose.
Современное лечение ВИЧ: новые парадигмы в АРТ / Contemporary Management of H...hivlifeinfo
Набор слайдов c рассмотрением важных вопросов об АРТ первого ряда, арв-препаратами пролонгированного действия и схемами АРТ с двумя препаратами, акцент в публикации на роль новых стратегий.
Annovis Bio is a clinical-stage, drug platform company addressing neurodegeneration, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Alzheimer’s in Down Syndrome (AD-DS). Annovis is believed to be the only company developing a drug for AD, PD and AD-DS that inhibits
more than one neurotoxic protein and improves the information highway of the nerve cell, known as axonal transport. When this information flow is impaired, the nerve cell gets sick and dies. The company expects its treatment to improve memory loss and dementia associated with AD and AD-DS, as well as body and brain function in PD. Annovis has an ongoing
Phase 2a study in AD patients and a second Phase 2a study in early PD and early AD patients.
Similar to Update on Neurocognitive Complications of HIV Disease (20)
Katherine Promer Flores, MD (she/her)
Staff Physician
Division of Infectious Diseases and Global Public Health
Department of Medicine
University of California San Diego
Daniel Lee, MD
Clinical Professor of Medicine
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Leandro Mena, MD, MPH
Chair and Professor of Population Health Science
Department of Population Health Science
University of Mississippi Medical Center
Maile Young Karris, MD
Associate Professor
Co-Director San Diego Center for AIDS Research Clinical Investigations Core
Divisions of Infectious Diseases & Global Public Health and Geriatrics & Gerontology
Department of Medicine
University of California San Diego
Edward Cachay, MD, MAS
Professor of Medicine
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Gabriel Wagner, MD
Associate Clinical Professor
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Jocelyn Keehner, MD
Infectious Disease Fellow
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Richard Garfein, PhD, MPH
Professor
Herbert Wertheim School of Public Health and Human Longevity Science
Adjunct Professor
Division of Infectious Disease and Global Public Health
Department of Medicine
University of California, San Diego
Laura Bamford, MD, MSCE
Associate Professor of Medicine
Medical Director, Owen Clinic
Division of Infectious Diseases and Global Public Health
Department of Medicine
University of California, San Diego
Davey Smith, MD, MAS
Professor of Medicine
Chief, Division of Infectious Diseases and Global Public Health
Co-Director, San Diego Center for AIDS Research (CFAR)
Department of Medicine
University of California, San Diego
Elliot Welford, MD
Infectious Diseases Fellow
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Darcy Wooten, MD
Assistant Professor of Medicine
Associate Program Director, Infectious Diseases Fellowship
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
Amutha Rajagopal, MD
Associate Physician Diplomate
Division of Infectious Diseases & Global Public Health
Department of Medicine
University of California, San Diego
More from UC San Diego AntiViral Research Center (20)
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
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Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
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Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
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Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Update on Neurocognitive Complications of HIV Disease
1. The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinicians, physicians and
researchers. The goal of these presentations is to provide the most
current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.
The slides from the AIDS Clinical Rounds presentation that you are
about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.
AIDS CLINICAL ROUNDS
3. Acknowledgements & Disclosures
UC San Diego
• Ronald J. Ellis
• J. Allen McCutchan
• Igor Grant
• Robert Heaton
• Donald Franklin
• Florin Vaida
• Edmund Capparelli
• Brookie Best
China CDC, Hospitals, & NSFC
• Zhang Fujie
• Yu Xin
• Wu Hao
• Zhao Hongxin
• Wu Weiwei
National
Institutes of
Health
! …Mental Health
! …Drug Abuse
! …Allergy and
Infectious Diseases
Industry
! ViiV Healthcare
! Abbvie
! Merck, Inc.
! Gilead Sciences
• Davey Smith
• David Moore
• Tom Marcotte
• Cris Achim
• Eliezer Masliah
• Mariana Cherner
• Melanie Crescini
• Debra Rosario
• Shi Chuan
• Zhang Hongwei
• Han Ning
• Zeng Hui
• Liu Xia
Study Volunteers
5. Definition of HAND
Acquired
Impairment in
≥ 2 Cognitive
Abilities
Interferes
with Daily
Functioning
No Cause
Prior to HIV
No Current
Strongly
Confounding
Condition
Asymptomatic
Neurocognitive
Impairment (ANI)
✔ No ✔ ✔
Mild
Neurocognitive
Disorder (MND)
✔ Mild ✔ ✔
HIV-Associated
Dementia (HAD)
Marked Marked ✔ ✔
Antinori et al, Neurology 2007, 69: 1789-99
6. Grant et al, Neurology 2014;82:1–8
• 347 adults who were either unimpaired (n = 226) or had ANI (n = 121)
• Assessed every 6 months with median follow-up of 45.2 months
• Symptomatic decline was based on self-report or objective, performance-based
problems in everyday functioning
• Current CD4 and depression were significant time-dependent covariates
• Not ART regimen, virologic suppression, or substance abuse or dependence
7. Challenges to the Implementation of the
Current Approach to HAND Diagnosis
• Screening instruments are not consistently
sensitive between sites
• We do not routinely perform comprehensive
neurocognitive testing in clinic
• Many of our patients are unemployed or have
below average socioeconomic status,
complicating assessment of daily functioning
• Confidently deciding that a condition
confounds attribution of the cause of
impairment to HIV can be difficult
8. Soluble Biomarkers Identify a
Preclinical Stage in Alzheimer’s
Sperling et al, Alzheimer’s & Dementia 7 (2011) 280–292
9. ANI and MND are Associated with
Higher Neopterin but not NFL
C S F N e o p te rin (n m o l/L )
CSFNFL(ng/L)
A N I/M N D
NPN
3.2 10 320
10
100
1000
10000 r = 0 .21
p < 0 .05
A .
)
1 0 0
* *
B .
CSFNeopterin(noml/L)
N P N A N I/M N D
1
1 0
1 0 0
* *
B .
Edén et al, CROI 2014, Abstract 490
• Cross-sectional analysis of 100 HIV+ subjects taking suppressive
ART without significant neuropsychiatric confounds
• Subjects were classified as NP-normal (NPN, n=79) or NP-impaired
(ANI, n = 38; MND, n=33)
p < 0.01
10. Higher Soluble CD163 in Plasma
in MND but not ANI
Burdo et al, AIDS 2013, 27:1387–1395
11. Higher HIV DNA Content is Associated
with Worse Neurocognitive Performance
Shiramizu et al, Int J Med Sci 2006, 6;4(1):13-8
Oliveira et al, CROI 2015, Abstract 491
A
0.0 0.5 1.0 1.5
0
10
20
30
40
50
GDS
HIVDNA(sqrt[cps/millioncells])
( )
- ( )
( )
Younger
Older
< 40 yo
> 50 yo
Valcour V et al, Neurology, 2009. 72(11):992-8
12. Possible Biological
Classification of HAND
Abnormal
HIV DNA
in Blood
Abnormal
Neopterin
in CSF
Abnormal
sCD163
in Plasma
Abnormal
Neurofilament
Light
in CSF
Evidence of
Another
Diagnosis on
Imaging
Asymptomatic
Neurocognitive
Impairment (ANI)
✔ ✔ No No No
Mild
Neurocognitive
Disorder (MND)
✔ ✔ ✔ No No
HIV-Associated
Dementia (HAD) ✔✔ ✔✔ (✔✔) ✔ No
Additional challenges:
• Clinical standardization of assays
• Identification of clinically relevant cutpoints
13. CSF/Plasma Albumin Ratio is
Elevated in HAND
Neuroasymptomatic, off ART
On ART
Anesten et al, CROI 2015. Abstract 59
p < 0.001
14. BBB Permeability During ART May
Define Different HAND Phenotypes
CHARTER Data, Manuscript in Preparation
15. Update on HAND Management
(you knew I’d have to talk
about CPE, didn’t you?)
16. N NP Duration Principal Finding Notes
Ciccarelli1 C-S 101 C - Beneficial
2010 version stronger than
2008 version
Ciccarelli2 C-S 215 C - Beneficial Adjusted CPE using GSS
Casado3 C-S 69 B - Trend toward benefit Beneficial when CD4 < 200
Vassallo4 L 96 C 22 months Beneficial
~25% were not virologically
suppressed
Cross6 L 69 C ~1 year No association Binary transformation only
Ellis5 RCT 49 C 16 weeks No association Beneficial in subgroup
Wilson7 C-S 118 B - Detrimental on 2 tests
Binary transformation only
Substance users only
Kahouadji8 C-S 93 B - Detrimental on 1 test Methodological flaws
Caniglia9 L 61,938 N - Detrimental Absolute risk 1.1% vs. 0.9%
Recent CPE Reports Have Mixed Findings
1Ciccarelli et al, Antiviral Therapy 2013, 18: 153-160; 2Ciccarelli et al, 20th CROI 2013, Abstract 405;
3Casado et al, J Neurovirol 2014, 20: 54-61; 4Vassallo et al, AIDS 2014, 28(4):493-501; 5Ellis et al, Clin
Infect Dis. 2014;58(7):1015-22; 6Cross et al, S Afr Med J 2013;103(10):758-762; 7Wilson et al, J Clin
Experim Neuropsych 2013, 35:915-25, 8Kahouadji et al, HIV Medicine 2013, 14: 311-5.
C-S = Cross-sectional, L = Longitudinal, RCT = Randomized clinical trial, C = Comprehensive, B = Brief,
N = None, GSS = Genotype Susceptibility Score
17. Two Uncontrolled Longitudinal Studies Found
Similar Effect Sizes but Came to Different
Conclusions
South Africa
Cross et al, S Afr Med J 2013;103(10):758-762
France
Vassallo et al, AIDS 2014, 28(4):493-501
Graph is adapted from Table 2
OR = 0.64
Odds ratio is calculated from data in the manuscript
Odds ratios from multivariable regression:
• Initial (first) CPE: 0.54
• End-of-follow-up (last) CPE: 0.65
15.8%22.6%
N = 69
N = 96
18. Major Findings
• 235 “HAD” events in 259,858
person-years of follow-up
– 1 per 1,106 person-years
• “High” CPE group had a 74%
increased hazard ratio of “HAD”
Caniglia et al, Neurology 2014;83:1–8; Berger & Clifford, Neurology 2014;83:1–2
Design
• Data from 61,938 patients
combined from 9 independent
HIV cohorts from Europe and
the U.S.
• Patients were evaluated prior
to ART initiation between 1998
and 2013
• “Intent-to-treat”-like analysis
based on initial regimen
• CPE transformed into 3
categories
– “Low”: ≤ 7
– “Medium”: 8-9
– “High”: ≥ 10
19. • Excluded subjects from 4 cohorts that had no neuroAIDS events
• Did not use standardized assessments for diagnosing “HAD”
– “…diagnostic procedures that reflect standard clinical practice”
• Categorical transformation of CPE is unusual
– Only 8.8% were in the “high CPE” group (≥ 10)
– No statistically significant association was found when CPE was analyzed
continuously or as a 4-category variable
• Between-group difference in absolute risk is not clinically
meaningful: 1 “HAD” case per > 4,500 person-years of follow-up
• Does not account for important factors:
– Changes in ART over time: 68% changed their initial regimen during
observation
– Non-HIV causes of neurocognitive disease: psychiatric disease,
substance use, co-infections
Caniglia et al, Neurology 2014;83:1–8; Berger & Clifford, Neurology 2014;83:1–2
20. Ideal Characteristics of Analyses
of CNS Effectiveness of ART
• Studies should be randomized and
longitudinal
• Power and duration should be sufficient
to test the hypothesis
• Assessments should be standardized and
comprehensive
• Drug regimen potency and toxicity of
comparator regimens should be similar
– For those that focus on CPE, regimens should
have the same number of drugs
21. Clinical Trial of CNS Penetrating ART
to Prevent HAND in China
R
Efavirenz + Tenofovir
+ Lamivudine (CPE 6)
Nevirapine + Zidovudine
+ Lamivudine (CPE 10)
250 HIV+ Adults
ART Naive, CD4 < 350/mm3
Normal Neurocognitive Performance
Follow-up: 96 Weeks at 2 Hospitals in Beijing
Safety Assessments & Data Safety Monitoring Board
Standardized Neurocognitive Testing
Functional Assessments
Targeted Pharmacogenetics
Inflammation Biomarkers in Blood
Open%Label*
Blinded to
Treatment Arm:
Investigators from
US, China CDC,
and Beijing
University Mental
Health Institute
!
22. Neurocognitive Methods
• An 8-test battery that
assessed 5 cognitive
abilities was administered
at 48 and 96 weeks
• Cross-sectional &
longitudinal normative data
– Adjust for effects of age, gender,
and education using data from
HIV- adults in China
• Summary measures
– Primary outcome: Summary
Change Score*
– Secondary outcomes: Global
neurocognitive impairment,
Global deficit score
Neurocognitive Test Battery
• Hopkins Verbal Learning Test-
Revised - Total Learning
• Brief Visuospatial Learning
Test-Revised - Total Learning
• WAIS-III Digit Symbol Test
• Grooved Pegboard Test
• WMS-III Spatial Span
• Action Fluency Test
• Paced Auditory Serial
Addition Task (PASAT)-50
*Cysique et al, J Clinical Experimental Neuropsychology 2011. 33 (5), 505–522
23.
24. Before Treatment,
Arms were Comparable
NVP-ZDV-3TC EFV-TDF-3TC P Value
Sample Size 128 122 -
Demographic Characteristics
Age (Years) 32.9 (7.7) 31.9 (8.3) 0.31
Sex (Men) 124 (97%) 122 (100%) 0.12
Ethnicity (Han) 121 (94.5%) 116 (95.1%) 0.84
Education (Years) 11.6 (3.6) 11.8 (3.9) 0.72
Body Mass Index 22.3 (2.9) 21.8 (2.5) 0.16
Disease Characteristics
AIDS Diagnosis 42 (32.8%) 39 (32.0%) 0.89
HIV RNA, Plasma (log10 c/mL) 4.2 (0.8) 4.2 (0.9) 0.78
CD4+ T-cells (/mm3) 235.1 (89.8) 222.1 (83.6) 0.24
CD8+ T-cells (/mm3) 823.6 (355.7) 836.2 (439.0) 0.80
HCV Seropositive 3 (2%) 3 (2%) 0.99
HBV Surface Antigen 1 (0.8%) 1 (0.8%) 0.99
*Values are either mean (SD), median [IQR], or number (%)
25. Before Treatment,
Arms were Comparable
NVP-ZDV-3TC EFV-TDF-3TC P Value
Sample Size 128 122 -
Neurocognitive & Mood Characteristics
Global Deficit Score (GDS) 0.12 (0.15) 0.14 (0.14) 0.25
Beck Depression Inventory 9.8 (7.6) 9.7 (8.3) 0.92
Other Lab Characteristics
Total WBC Count (x 109/L) 5.1 (1.5) 4.9 (1.3) 0.55
Hemoglobin (g/dL) 14.7 (1.1) 14.8 (1.2) 0.55
Platelets (x 109/L) 191 (51) 187 (46) 0.57
Alanine Aminotransferase, Serum 22.9 [16.0, 33.8] 21.1 [15.0, 30] 0.24
Total Bilirubin, Serum 0.12 (0.05) 0.12 (0.04) 0.46
Albumin, Serum 4.7 (0.3) 4.7 (0.4) 0.76
Total Protein, Serum 8.2 (0.5) 8.2 (0.6) 0.92
Creatinine, Serum 0.73 (0.10) 0.73 (0.11) 0.68
*Values are either mean (SD), median [IQR], or number (%)
26. On Treatment, Indicators of
Antiviral Efficacy Were Comparable
NVP-ZDV-3TC EFV-TDF-3TC P Value
Sample Size 114 119 -
HIV RNA, Plasma (No. (%) ≤ 50 c/mL) 103 (91.2%) 109 (91.6%) 1.00
CD4+ T-cells (/µL) 396.6 (158.0) 396.5 (153.4) 1.00
CD8+ T-cells (/µL) 789.4 (368.0) 760.5 (360.8) 0.54
100% Adherence in Past 4 Days 113 (99.1%) 119 (100%) 0.49
Week 48 (ITT-Completer)
Week 96 (ITT-Completer)
NVP-ZDV-3TC EFV-TDF-3TC P Value
Sample Size 112 118 -
HIV RNA, Plasma (No. (%) ≤ 50 c/mL) 104 (92.0%) 112 (95.7%) 0.28
CD4+ T-cells (/mm3) 447.2 (179.3) 483.8 (183.8) 0.13
CD8+ T-cells (/mm3) 811.3 (322.4) 850.6 (408.7) 0.42
100% Adherence in Past 4 Days 112 (100%) 116 (100%) 1.00
*Values are either mean (SD), median [IQR], or number (%)
27. EFV-TDF-3TC Was Associated with
Greater Decline After 96 Weeks
ITT-C Analysis, N = 233 As Treated Analysis, N = 187
28. EFV-TDF-3TC Was Associated with
Shorter Time-to-Impairment
ITT-C Analysis, N = 233 As Treated Analysis, N = 187
29. 107 Subjects Had at Least
One Adverse Event
NVP-ZDV-3TC EFV-TDF-3TC P value
Subjects with at least 1 Adverse Event* < 0.001
66 (57.9%) 41 (34.4%)
Most Severe Adverse Event Grade* 0.006
- Grade 1 19 (16.7%) 25 (21.0%)
- Grade 2 15 (13.2%) 8 (6.7%)
- Grade 3 18 (15.8%) 5 (4.2%)
- Grade 4 14 (12.3%) 3 (2.5%)
Adverse Event-Related Discontinuations* < 0.001
41 (32%) 1 (0.8%)
*Denominator is Number of Subjects in the ITT-C Analysis
• All Adverse Event-Related Discontinuations Occurred before
28 Weeks
30. Liver toxicity, Hypersensitivity, and
Bone Marrow Suppression Were More
Common with NVP-ZDV-3TC
NVP-ZDV-3TC EFV-TDF-3TC P value
Elevated ALT or AST 40 (35.1%) 23 (19.3%) 0.008
Rash 24 (21.0%) 3 (2.5%) < 0.001
Neutropenia/Leukopenia 20 (17.5%) 5 (4.2%) 0.001
Fever 13 (11.4%) 1 (0.8%) < 0.001
Anemia 9 (7.9%) 0 (0%) 0.001
Thrombocytopenia 6 (5.3%) 5 (4.2%) 0.76
Hyponatremia/Hypokalemia 3 (2.6%) 9 (7.6%) 0.08
• All adverse events were reversible
• 14 (6.0%) hospitalizations occurred
• 8 were considered “Definitely Related” to study treatment
• No deaths occurred
*Denominator is Number of Subjects in the ITT-C Analysis
31. Adverse Events and
Discontinuations Differed by Site
Site 1 Site 2 P value
Sample Size 138 95 -
Subjects with
≥ 1 Adverse Event
69 (50%) 38 (40%) 0.14
Most Severe Adverse Event Grade* 0.003
- Grade 1 33 (47.8%) 11 (28.9%)
- Grade 2 19 (27.5%) 4 (10.5%)
- Grade 3 10 (14.5%) 13 (34.2%)
- Grade 4 7 (10.1%) 10 (26.3%)
Discontinuations Per Subject with Adverse Events by Arm* < 0.001
19/69 (27.5%) 23/38 (60.5%)
*Denominator is Number of Subjects with Adverse Events at each Site
• Data Safety Monitoring Board recommended early termination
of enrollment at Site 2
32. Sites Differed in Other
Characteristics
Site 1 Site 2 P Value
Sample Size 138 95 -
Demographic Characteristics
Age (Years) 33.3 (8.6) 31.4 (7.2) 0.07
Education (Years) 9 [9-12] 14 [9-16] < 0.001
Sex (Number (%) Men) 134 (97.8%) 94 (98.9%) 0.65
Ethnicity (Number (%) Han) 133 (96.4%) 89 (93.7%) 0.72
HIV Disease Characteristics
AIDS Diagnosis 51 (21.9%) 27 (28.4%) 0.15
HIV RNA, Plasma (log10 c/mL) 4.2 (0.9) 4.2 (0.8) 0.57
CD4+ T-cells (/mm3) 225.8 (78.9) 227.4 (85.0) 0.89
Other Lab Characteristics
Hemoglobin 14.5 (11.2) 15.0 (11.0) < 0.001
Aspartate Transaminase, Serum 25.0 (8.1) 22.8 (11.2) < 0.001
Total Protein, Serum 8.0 (5.3) 8.3 (4.9) < 0.001
*Values are either mean (SD), median [IQR], or number (%)
33. EFV-TDF-3TC Was Associated with
Shorter Time-to-Impairment at Site 1
ITT-C Analysis, N = 138 As Treated Analysis, N = 118
34. Nested Case-Control Study of 15
Decliners and 15 Matched Non-Decliners
Ma et al, CROI 2015, Abstract 444
Antiretroviral
Drug Concentrations
Magnetic Resonance
Imaging/Spectroscopy
CSF
Biomarkers
35. Maraviroc Intensification
May Be Beneficial
• Open-label, single-arm intensification trial with
MVC In 12 adults on suppressive ART
• Reduced circulating intermediate and
nonclassical CD16-expressing monocytes,
monocyte HIV DNA content and sCD163 by
24 weeks
• This was associated with significant
improvement in NP performance in the 6
subjects who had mild to moderate cognitive
impairment.
• 12 month prospective open-label,
randomized, placebo-controlled trial
• 14 adults on suppressive ART with recent
progression to HAND completed the trial
• Large effect (d 0.77) at 6-months and
moderate effect at 12-months (d 0.55)
– Arm x Time interaction: p < 0.05
• Glutamate concentration in BG was stable
in MA arm but increased in control arm at
12-months
Ndhlovu et al, J Neurovirol. 2014;20(6):571-82 Gates et al, CROI 2015. Abstract 441
36. DHHS Preferred Regimens (ART Naive)
TDF%FTC*
EFV1*
ATV/r1*
DRV/r*
RAL*
• Short- and long-term neurotoxicity
• CSF concentrations do not consistently
exceed inhibitory concentrations
• Associated with CSF viral escape
• CSF concentrations exceed 50%
inhibitory concentrations in all
• CSF concentrations exceed 50%
inhibitory concentrations in all
EVG/c* • No CSF pharmacokinetic data
DTG*
• CSF concentrations exceed 50%
inhibitory concentrations in all
• Fewer CNS side effects than EFV
DTG*ABC%3TC* • No CSF ABC pharmacokinetic data on
daily dosing
RPV2*
• CSF concentrations do not consistently
exceed inhibitory concentrations
1May be combined with ABC-3TC when HIV RNA < 100,000 copies/mL; 2In patients with HIV RNA
< 100,000 copies/mL; Last updated 1 May 2014; Available at http://www.aidsinfo.nih.gov/guidelines
37. TDF%FTC*
EFV1*
ATV/r1*
DRV/r*
RAL*
EVG/c*
DTG*
DTG*ABC%3TC*
1May be combined with ABC-3TC when HIV RNA < 100,000 copies/mL; 2In patients with HIV RNA
< 100,000 copies/mL; Last updated 1 May 2014; Available at http://www.aidsinfo.nih.gov/guidelines
RPV2*
DHHS* EACS* BHIVA* WHO*
︎* ︎* ︎* ︎*
︎* ︎* ︎*
︎* ︎* ︎*
︎* ︎* ︎*
︎* ︎* ︎*
︎* ︎*
︎* ︎*
︎* ︎*
39. ART Drug Concentrations in Brain:
Regional Variation, CSF Comparability
n
Overall
Mean
WM
(mean)
GP
(mean)
CGM
(mean)
Concentrations Similar to Historical CSF Concentrations
Atazanavir (ATV) 2 < 25 < 25 < 25 < 25
Efavirenz (EFV) 2 38.6 45.2 34.8 35.9
Emtricitabine (FTC) 4 181.3 230.4 173.2 140.3
Lamivudine (3TC) 3 196.9 205.5 209.8 175.4
Concentrations in White Matter Higher than Historical CSF Concentrations
Lopinavir (LPV) 4 153.3 410.6 < 25 < 25
Concentrations Higher than Historical CSF Concentrations
Tenofovir (TDF) 6 206.0 220.0 212.1 185.8
WM = White Matter; GP = Globus Pallidus (Deep Gray Matter); CGM = Cortical Gray Matter
Bumpus et al, CROI, 2015, Abstract 436
Concentration units are ng/mL
40. Suppressive ART protects against
neurodegeneration in CNTN
BetterWorse
CombinedNeurodegenerationScore
(MAP2,SYN)
ARV
Naive
cART
Failure
cART
Success
Bryant et al, AIDS 2015, 29(3):323-30
41. Protease Inhibitor Use is Associated
with Cerebral Small Vessel Disease
• 144 adults with HIV/AIDS who died
between 1999 and 2011 and had been
evaluated prior to death in CNTN
• Protease inhibitor use was associated
with cerebral small vessel disease
– Mild: OR 2.8 (95% CI 1.03–7.9)
– Moderate-severe: 2.6 (95% CI 1.03–6.7)
• Mild CSVD was associated with HAND
– OR 4.8 (95% CI 1.1–21.2)
Soontornniyomkij et al, AIDS 2014, 28:1297–1306
42. HIV RNA in CSF May Increase
Risk for New Onset Depression
0.1
1
10
Unadjusted Model 1 Final Model
HazardRatiosforDepression
CSF Plasma
Model 1: Adjusted for CSF/Plasma HIV RNA and adherence
Final model: Adjusted Model 1 for lifetime MDD, lifetime alcohol and substance abuse,
duration of ART, CPE, age, sex, race
*
**p < 0.0120
5
2
Error bars
are 95%
confidence
intervals
Hammond et al, CROI 2014, Abstract 33
43. Exercise & Cognitive Rehabilitation
May Improve HAND
Dufour et al, J Neurovirol 2013,
DOI 10.1007/s13365-013-0184-8
Exercisers had lower odds of having
global neurocognitive impairment
(OR= 0.38, p < 0.05)
Weber et al., Neuropsychol Rev 2013,
DOI 10.1007 s11065-013-9225-6
Strategic imagery improved
prospective memory
44. Summary & Conclusions
• Published reports of the cognitive effects of ART
continue to have inconsistent findings
– Substantial variation in methods
– Few studies use ideal methods or have sufficient power to address
the questions
• Randomized clinical trial in China supports differences
in two ART regimens in preventing HAND
– Effect sizes are small to medium
– May be due to both ineffectiveness and toxicity in the CNS
• BBB permeability may define different HAND
phenotypes that may inform clinical management
– Independent confirmation is needed
• Selecting the “right” ART for the CNS should consider
effectiveness and toxicity outside the CNS
45. Please Help Us
AVRC: 619-543-8080
• ACTG 5324
– Patients with HAND on
suppressive ART
– Randomized to
addition of placebo,
dolutegravir, or
dolutegravir+maraviroc
• CSF Stribild
– ART naive patients will
to start ART
– No HAND requirement
• CNS HCV DAA
– Genotype 1 HCV
– HIV- or HIV+
– No active drug use for
3 months
– Will provide sofosbuvir
and ledipasvir
HNRC: 619-543-5050
• California
NeuroAIDS Tissue
Network
– Brain bank study for
patients with more
advanced disease
46.
47. Other Characteristics May Influence the
ART Efficacy & Safety in the CNS
Shikuma et al, Antiviral Therapy
2012, 17: 1233-42
Robertson et al, J Neurovirol
2012, 18: 388-299
Monocyte Efficacy Neuronal Toxicity
48. CPE (1-4)
Higher is Better
ME (3-333)
Higher is Better
Toxicity Index
Lower is Better
Zidovudine 4 50 -0.75
Tenofovir 1 50 -0.25
Abacavir 3 3 +2.75
Lamivudine 2 50 +0.40
Emtricitabine 3 12.5 -0.75
Efavirenz 3 100 -0.10
Nevirapine 4 20 +1.75
Atazanavir 2 - +0.75
Darunavir 3 - -1.50
Lopinavir 3 - -
Maraviroc 3 - -1.90
Raltegravir 3 - -
Combined Characteristics May Alter
Estimates of CNS Effectiveness
49. CPE (1-4)
Higher is Better
ME (3-333)
Higher is Better
Toxicity Index
Lower is Better
Zidovudine 4 50 -0.75
Tenofovir 1 50 -0.25
Abacavir 3 3 +2.75
Lamivudine 2 50 +0.40
Emtricitabine 3 12.5 -0.75
Efavirenz 3 100 -0.10
Nevirapine 4 20 +1.75
Atazanavir 2 - +0.75
Darunavir 3 - -1.50
Lopinavir 3 - -
Maraviroc 3 - -1.90
Raltegravir 3 - -
Combined Characteristics May Alter
Estimates of CNS Effectiveness
50. CPE (1-4)
Higher is Better
ME (3-333)
Higher is Better
Toxicity Index
Lower is Better
Zidovudine 4 50 -0.75
Tenofovir 1 50 -0.25
Abacavir 3 3 +2.75
Lamivudine 2 50 +0.40
Emtricitabine 3 12.5 -0.75
Efavirenz 3 100 -0.10
Nevirapine 4 20 +1.75
Atazanavir 2 - +0.75
Darunavir 3 - -1.50
Lopinavir 3 - -
Maraviroc 3 - -1.90
Raltegravir 3 - -
Combined Characteristics May Alter
Estimates of CNS Effectiveness
52. Summary
• EFV-TDF-3TC was associated with greater
neurocognitive decline over 96 weeks than
NVP-ZDV-3TC
• These long-term effects were offset by adverse
events of other organs that were short-term and
reversible but sometimes severe
– Power was substantially reduced in as-treated analyses
by greater than projected NVP-ZDV-3TC
discontinuations, most prominently at one site
• In a supplemental project, drug concentrations,
magnetic resonance imaging, and inflammation
biomarkers differed by either neurocognitive decline
or treatment arm
53. Acknowledgements
• Melanie Crescini
• Robert Heaton
• Hua Jin
• Florin Vaida
Beijing University
• Chuan Shi
• Xin Yu
• Psychometrists
Study Volunteers
Ditan Hospital
• Hongxin Zhao
• Ning Han
• Hui Zeng
• Xia Liu
China CDC
• Fujie Zhang
• Weiwei Zhang
• Yao Zhang
• Weiwei Mu
Youan Hospital
• Hao Wu
• Hongwei Zhang
• Donald Franklin
• Rachel Schrier
• Katie Riggs
• Yeng Wu
Univ. at Buffalo
• Qing Ma
UC San Diego
Data and Safety Monitoring Board
54. Supplemental Project of 30
Subjects Was Performed
• 15 Neurocognitive Decliners were
matched to 15 Non-Decliners for age,
education, ethnicity, and baseline NC
performance
– Decline determined at Week 48
• 23 successfully underwent lumbar
puncture
– ART drug concentrations were measured in
matched blood and CSF specimens
55. Cases & Controls were Comparable
Non-Decliners Decliners P Value
Sample Size 11 12 -
Global Deficit Score 0.11 (0.15) 0.76 (0.25) < 0.0001
Age (years) 32.8 (6.3) 33.0 (8.8) 0.95
Sex (men) 11 (100%) 12 (100%) 1.00
Randomized Regimen 0.54
- EFV-TDF-3TC 5 (45.5%) 7 (58.3%)
- NVP-ZDV-3TC 6 (54.5%) 5 (41.7%)
Post-Dose Sampling Time 12.9 (5.4) 10.6 (4.7) 0.28
Baseline HIV RNA, Plasma
(log10 c/mL)
4.5 (0.6) 4.3 (0.9) 0.51
Current HIV RNA, Plasma
(Number (%) ≤ 50 c/mL)
10 (90.9%) 11 (91.7%) 0.95
Current CD4+ T-cells (/mm3) 360.1 (92.5) 418.0 (136.8) 0.24
Nadir CD4+ T-cells 229.9 (59.3) 256.3 (49.5) 0.26
Ma et al, CROI, 2015, AcceptedFunded by NIH R01 MH92225 (PI: Letendre)
56. Cases & Controls Differed by
CSF-Plasma Ratios of EFV & TDF
TDF*CSF%to%Plasma*
RaDo*≥*0.038*
3*Decliners*
0*Non%Decliners*
No Yes
EFV*CSF%to%Plasma*
RaDo*≥*0.0057*
0*Decliners*
5*Non%Decliners*
No Yes
4*Decliners*
1*Non%Decliners*
Correctly classified
12 of 13 (92.3%) subjects
Ma et al, CROI, 2015, Accepted
57. Inhibitory, Toxic, and Pharmacologic
Concentrations Vary By Drug
Drug Concentration
Effect
• It does not necessarily follow that a drug that reaches
more efficacious concentrations in the CNS will also
reach more toxic concentrations
Inhibition of HIV Replication Neurotoxicity Concentration Range
58. Lipid Profiles are Associated with BBB
Permeability, Which is Associated with
Drug Distribution into CSF
-0.5 0.0 0.5 1.0
0.00
0.25
0.50
0.75
1.00
1.25
LDL-HDL Ratio (log10)
CSF-SerumAlbuminRatio(log10)
r = 0.33
p < 0.0001
59. PBMC HIV DNA Increase with Worsening
Cognition among ARV-experienced
Subjects
HIV DNA in HAHC Study
Neurocognitive Group
1 2 3 4
LogHIVDNACopies/10(6)PBMC
-1
0
1
2
3
4
5
6
7
Normal Neuropsych Minor Motor HIV Dementia
Abnormal Cog Disorder
LogHIVDNA(copies/10(6)PBMC
Shiramizu!et!al.,!AIDS,!2005!
60. High PBMC HIV DNA associated with
Dementia irrespective of plasma HIV RNA
All!Subjects!! Subjects!with!
!HIV!RNA<50!copies/ml!
NonCDemented!!!Demented!!!!!!!!!!!!!!!!!!!!!!!!!!NonCDemented!!!!Demented!
Log!HIV!DNA!(copies/10(6)!PBMC!
Log!HIV!DNA!(copies/10(6)!PBMC!
Shiramizu!et!al.!AIDS,!2005!
61. HIV DNA by
CD14-, CD14+CD16- ,
and CD14+CD16+
Monocyte Subsets
(n=68)
D14-
LogHIVDNACopies/106CD14+CD16-
(n=20) (n=16) (n=32)
(n=68)CD14+CD16-
CD14-
(n=68)
(n=20) (n=16) (n=32)
LogHIVDNACopies/106CD14+CD16+
CD14+CD16+
(n=68)
(n=20) (n=16) (n=32)
LogHIVDNACopies/106CD14-
(n=20) (n=16) (n=32)
CD14-
(n=20) (n=16) (n=32)
Kusao!I!et!al,!J!Neropsychiatry!Clin!Neurosc,.!2012!!
62. Monocyte (CD14+) HIV DNA by Clinical
Dementia Classification in ART-naïve
Subjects
Valcour!!V!et!al.!Plos!One,!2013!
!
63. Following Initiation of ART, Monocyte (CD14+)
HIV DNA in Individuals with Dementia remain
High
Visit!(Years))!
Monocyte!(CD14+)!HIV!DNA!
!!!!!Entry!!0.5!!!!1.5!!!!!2!!!!!2.5!!!!3!!!!!3.5!!!!!4!!
Shiramizu!et!al.!Journal!of!NeuroVirology.,!2012!
◌ Non-Demented
● Demented!
64. Detectable HIV DNA is associated with
Regional Brain Atrophy
Kallianpur!et!al.,!!Neurology!2013!
66. Monocyte HIV DNA correlates with
plasma and CSF Neopterin Levels
Valcour!!Plos!One,!2013!
!
67. Monocyte Efficacy (ME) Score
• The median effective concentration (EC50) [acute
infection] of each drug in primary macrophage cells.
• Constructed a ME score for each ART regimen,
defined as:
– Summed reciprocal score (x 1000) of each regimen's drug's
(EC50) [acute infection]
• Examined association of ME Score to cognitive
function within patients on stable HAART (n=137) in
the Hawaii Aging with HIV (HAHC) Cohort
Shikuma!et!al,!An]viral!Therapy!2012!!
70. Distribution of ME and CPE scores by
Clinical Cognitive Classification
CPE!Score!(P=0.01)*!!ME!Score!(p=0.001)*!
Shikuma!et!al!,!An]viral!Therapy!2012!
0100200300400
MEScore
Normal NP abnormal MCMD HAD
N=28 N=37 N=51 N=23
051015
CPEScore
Normal NP abnormal MCMD HAD
N=28 N=37 N=51 N=23
P=0.004!
P<0.001!
*!By!KruskalCWallis!
71. Probability of Diagnosis by Clinical
Cognitive Status
Shikuma!et!al.,!An]viral!Therapy!2012!
100!Unit!increase!in!ME!score!results!in!a!10.6x!decrease!in!OR!for!HAD;!
2.6x!decrease!in!OR!for!MCMD!!
72. Open-Label Single-Arm Maraviroc
Intensification Trial
• Maraviroc is a CCR5 antagonist; macrophage E50 (acute
infection) of 0.5nM = ME Score [(1/ EC50) x 1000] of 2000
• Study endpoints: CD14+ HIV DNA, monocyte subsets
and neuropsychological performance
Maraviroc*
wk!0!
(entry)!
wk!4! wk!12! wk!24!
15!HIV+!subjects!
• !!On!ART>1!yr!
• !!HIV!RNA!<!50!copies/ml!
• !!Detectable!PBMC!HIV!DNA!
!
73. Decrease in Monocyte (CD14+) HIV DNA
following Maraviroc Intensification
Ndhlovu!L,!CROI!2013!
75. No change in Classical MO following
Maraviroc Intensification
!!!!!!!!!!Classical!MO!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
∆!Wl0C24,!p=0.21!
Weeks!postCMVC,!
Median!(IQR),!
P!value!by!Wilcoxon!Test!
%!Frequency!MO!Subset!
Wk!0!!!!!!!4!!!!!!!!!!!!!!!!!12!!!!!!!!!!!!!!!!!!!24!
76. Change in % Intermediate MO following
Maraviroc Intensification
∆!Wk0C24!
P=0.027!
Weeks!postCMVC,!
Median!(IQR),!
P!value!by!Wilcoxon!Test!
Intermediate!MO!(CD14++CD16+)!!
∆!Wk0C12!
P=0.32!
∆!Wk0C4!
P=0.74!
%!Frequency!MO!Subset!
!!!!!!!!! !!!!!!!!!!!
Wk!0!!!!!!!4!!!!!!!!!!!!!!!!!12!!!!!!!!!!!!!!!!!!!!!!!!!24!
∆!Wk0C24!
P=0.042!
77. Change in Non-Classical MO following
Maraviroc Intensification
!!!!!NonCClassical!MO!(CD14+/loCD16++)!!
%!Frequency!MO!Subset!
∆!Wk0C4!
P=0.46!
∆!Wk0C12!
P=0.23! ∆!Wk0C24!
P=0.027!
!!!!!!!!! !!!!!!!!!!!
Wk!0!!!!!!!4!!!!!!!!!!!!!!!!!12!!!!!!!!!!!!!!!!!!!!!!!!!24!
Weeks!postCMVC,!
Median!(IQR),!
P!value!by!Wilcoxon!Test!
80. Integrating Recent Findings into
the Classification of HAND
Abnormal
CSF
Neopterin
Abnormal
Plasma
sCD163
Abnormal
CSF
Neurofila-
ment Light
Impaired
NP
Testing
Impaired
Daily
Functioning
No
Pre-HIV
Cause
No Current
Confounder
Preclinical:
At Risk for
HAND
✔ No No No No ✔ ✔
Asymptomatic
Neurocognitive
Impairment (ANI) ✔ No No ✔ No ✔ ✔
Mild
Neurocognitive
Disorder (MND)
✔ ✔ No ✔ Mild ✔ ✔
HIV-Associated
Dementia (HAD) ✔✔ (✔✔) ✔ Marked Marked ✔ ✔