HIV AND NEUROCOGNITIVE DISORDERS MANAGEMENT

DECEMBER 5, 2019

Leleka Doonquah, MDInternal Medicine/Infectious Diseases

CME Disclosures: Planning Committee And Speaker

Speaker: The following speaker has nothing to disclose in relation to this activity: Leleka Doonquah, MD

Howard UniversityCME Accreditation

Sponsor Accreditation: Howard University Collegeof Medicine is accredited by the Accreditation Council

for Continuing Medical Education to provide continuingmedical education for physicians.

Credits for Physicians: Howard University Collegeof Medicine, Office of Continuing Medical Education,

designates this live activity for a maximum of 1.0 AMAPRA Category I Credit(s)TM . Physicians should claim

only the credit commensurate with the extent of their participation in the activity.

Goulda A. Downer, PHD, RD, LN, CNS – Principal Investigator/Project Director

CME Disclosures: Planning Committee And Speaker

AETC-Capitol Region Telehealth ProjectPlanning Committee: The following committee members have nothing to disclose in relation to this activity:

Goulda A. Downer, PhD, FAND, RD, LN, CNS Dr. Walter P. Bland, Assistant Dean, CMEJohn I. McNeil, MDDenise Bailey, M.EDMarjorie Douglas

Speaker: The following speaker has nothing to disclose in relation to this activity: Leleka Doonquah, MD

Howard University CME Accreditation Requirements For Internet Viewers

Intended Audience: Health service providers: Physicians, Physician Assistants, Nurse Practitioners, Pharmacists,

Dentists, Nurses, Social Workers, Case Managers and other Clinical Personnel.

Webinar Requirements: A computer, phone, etc., with internet accessibility and a telephone line.

ØYour presence on the call must be acknowledged at the start of each session. Please log in for the session. Announce

your name loud and clear, at the beginning of the session.

ØYou will not be able to receive CME credits if you leave the session early.

ØAt the end of the Webinar, our Training Coordinator will email a CME Evaluation Survey.

ØAll participants are required to complete and return the CME Evaluation Survey at the end of each session. It

may be scanned and emailed back to den_bailey@howard.edu, or faxed to: AETC-Capitol Region Telehealth Project

(FAX#: 202.667.1382) ATTN: Project Coordinator. Please indicate in your email or FAX if you would like to receive CMEs.

GILEAD SCIENCES INC. FUNDING AND DISCLOSURE

“Supported by grant funding from Gilead Sciences, Inc. has no input into the development or content of these materials.”

HIV AND NEUROCOGNITIVE DISORDERS MANAGEMENT

LEARNING OBJECTIVES

By the end of this session, participants will be able to:

1. Define the spectrum of HIV associated Neurocognitive Disorders (HAND)

2. Discuss prevalence and incidence of HAND in the era of highly active antiretroviral therapy (ART)

3. Recognize risk factors for HAND

4. Identify treatment options for HAND

DEFINITION OF HIV NEUROCOGNITIVE ASSOCIATED DISORDERS

WHAT IS HIV NEUROCOGNITIVE ASSOCIATED DISORDER?

HIV-Associated Neurocognitive Disorders (HAND) refers to a spectrum of neurological diseases of the brain (HAND)

People living HIV may develop a spectrum of cognitive, motor, and/or mood problems collectively known as HIV-Associated Neurocognitive Disorder

Symptoms include difficulties with attention, concentration, and memory; loss of motivation; irritability; depression; and slowed movements

https://memory.ucsf.edu/sites/memory.ucsf.edu/files/wysiwyg/UCSF_HIV%20Dementia_Providers_11-6-17.pdf

https://www.poz.com/basics/hiv-basics/hiv-associated-neurocognitive-disorders-HAND

In 2007, the diagnostic criteria for HIV associated Neurocognitive disorders were revised (Ref).They are now listed/ defined as a spectrum of disorders.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260107/

HIV AND AIDS IN THE CARIBBEAN REGIONAL OVERVIEW

https://www.avert.org/professionals/hiv-around-world/latin-america/overview

ESTIMATED HIV INCIDENCE BY REGION IN ADULTS 15 TO 49 YEARS OF AGE, 2000 AND 2012

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724434/http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/UNAIDS_Global_Rep

Approximately one out of every four people living with HIV will suffer from HAND.

Almost 10 million people worldwide are believed to be living with neurocognitive disorders brought about by the HIV infection.

DID YOU KNOW?

https://www.sciencedaily.com/releases/2017/07/170720113652.htm

DEMENTIA IN THE CARIBBEAN REGION

By 2050, it is believed that some one million people in the Caribbean Region will be affected by Alzheimer’s Disease and other dementias.

Yet, there is limited information, advice, research, policy, advocacy, and support available for those who are affected, and their careers.

https://www.healthycaribbean.org/4th-caribbean-conference-on-alzheimers/

NEUROLOGIC DISEASE IN THE HIV PATIENT

CATEGORIES OF HIV-ASSOCIATED NEUROCOGNITIVE DISORDER

https://www.caregiver.org/hiv-associated-neurocognitive-disorder-hand

NEUROLOGIC DISEASES IN PATIENTS WITH HIV INFECTION

Opportunistic Infections

Ø ToxoplasmosisØ CryptococcosisØ Progressive Multifocal LeukoencephalopathyØ CytomegalovirusØ SyphilisØ Mycobacterium TuberculosisØ HTLV-1 InfectionØ Amebiasis

NeoplasmsØ Primary CNS lymphomaØ Kaposi’s Sarcoma

https://www.infectiousdiseaseadvisor.com/home/decision-support-in-medicine/infectious-diseases/neurologic-disease-in-the-hiv-patient/

• DEFINITION OF NEUROCOGNITIVE DISORDERS

NEUROLOGIC DISEASES IN PATIENTS WITH HIV INFECTION

HIV-1 Infection

ØAseptic meningitis

ØHIV-Associated Neurocognitive Disorders (HAND)

https://www.infectiousdiseaseadvisor.com/home/decision-support-in-medicine/infectious-diseases/neurologic-disease-in-the-hiv-patient/

ØMyelopathy

ØPeripheral neuropathy

ØMyopathy

ASYMPTOMATIC NEUROCOGNITIVE IMPAIRMENT (ANI)

ØAn acquired mild to moderate impairment in cognitive function

ØThe functional impairment has been seen for more than 1 month

ØThe impairment does not meet the criteria for delirium or dementia

ØThe cognitive impairment is not fully explained by comorbid conditions

MILD NEUROCOGNITIVE DISORDER (MND)

The spectrum includes interference with activities of daily living:o Attentiveness, especially when multitasking

o Planning, organizing and decision-making

o Learning

o Memory

o Language

o Perceptual-motor (translating perception into action)

o Ability to comprehend social cues and/or behave appropriately in social situations

https://www.baptisthealth.com/pages/services/behavioral-health/conditions-we-treat/major-and-mild-neurocognitive-disorder.aspx

HIV ASSOCIATED DEMENTIA (HAD)

This is the more severe state of the spectrum and in some literature is also known as AIDS dementia Complex ( ADC), or HIV Encephalopathy.

This includes a more marked cognitive impairment.

The inability to complete ADL’s independently.

EPIDEMIOLOGY

Since the introduction of highly active antiretroviral therapy (ART) in 1996 the incidence of HIV dementia (i.e. the more severe form within the spectrum) has dramatically decline by approximately 50% ( McArthur 2005)

However since the introduction of ART the prevalence of HAND has increased up to about 35%-40%, specifically the milder forms ANI & MND (Robertson 2007)

ETIOLOGY

ØStill not clear

ØHAND may be in part caused by residual injury from unsuppressed HIV viral replication in the brain prior to starting ART

PATHOGENESIS OF HAND

ØStill poorly understood

ØWhat is known:

o HIV enters the brain being carried by monocytes and lymphocytes that are able to cross the blood brain barrier

o In studies HIV has been shown to have a predilection of the basal ganglia, deep white matter and hippocampus thereby resulting in subcortical dementia. (versus cortical dementia )

Source is ‘Neurological Complications of HIV infections’ by Shelli Farhadia, Payal Patel Curr Infect Dis Rep. December 2017

CASE STUDY # 1

CASE STUDY #1

Ernest is 60-years old, and recently retired from the Hospitality and Tourism Industry after 35 years. He is originally from Grenada but left at age 25 to pursue a degree in Hospitality Management in Trinidad. After graduation he was hired by one of the top hotels and worked his way up to a senior managerial position. He was diagnosed with HIV nine years ago. He has had limited contact with his family in Grenada.

At the time of diagnosis, Ernest was very ill due to advanced HIV infection; he was hospitalized for several weeks and treated for severe pneumonia. Once stabilized his doctor suggested that he go abroad and get further tests and treatment. Ernest was also diagnosed with HIV-associated dementia (HAD). Ernest took a leave of absence and went to New York for treatment. Following successful treatment and initiation of HIV medicines, Ernest’s physical health and cognitive function steadily improved over the next year and returned to his job.

However, in the last two years Ernest’s physical health declined, and he worked a limited schedule at work. It is becoming difficult for Ernest to take care of himself, and he is concerned that his memory problems are getting worse. He forgets to turn off the stove after preparing a meal, has problems remembering phone numbers and his medical appointments; he rarely leaves his home and frequently appears disoriented. About twelve years ago in preparation for his retirement Ernest moved to a rural farming community. His neighbors in this small close-knit community are very helpful and assist when they can, but they are also concerned about him.

CONSIDER...

1. What were the first signs that Ernest had HIV-associated dementia?

2. What support can be provided to Ernest?

3. What strategies can be implemented to help Ernest maintain his neurocognitive functions?

CLINICAL MANIFESTATION

ØThe clinical features of HAND are mostly related to the involvement of HIV in the subcortical structures.

ØAffects the following 3 areas:

o Cognition

o Behavioral

o Motor function

COGNITION

ØMemory

ØConcentration

ØMental processing speed

ØComprehension

BEHAVIORAL

ØApathy

ØDepression

ØAgitation

ØMania

MOTOR FUNCTION

ØUnsteady gait

ØPoor coordination

ØAbnormal muscle tone

ØTremors

RISK FACTORS FOR HAND

ØHost genetic factors (like polymorphisms in the Apo lipoprotein E4, chemokine receptor CCR, monocyte chemo attractant protein-1)

ØHIV disease specific factors ( e.g., hx of AIDS defining illness, lack viral suppression, low CD4 nadir, HIV RNA levels in CSF, duration of HIV infection, older age at HIV seroconversion)

ØComorbidities ( > 50 years of age, anemia, vascular disease, metabolic abnormalities, hepatitis C co-infection)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039628/

CASE STUDY #2

CASE STUDY #2

A 62-year-old African American male was referred from a general practitioner to the ID provider for HIV care. Patient JR was diagnosed HIV+ many years prior and was treatment experienced, currently on Abacavir, lamivudine and ritonavir boosted duranavir bid. While under the care of his current ID provider JR remained relatively stable on his current ARV regimen maintaining a steady CD4 count ranging in the 700-900’s with a CD4% ranging 18%-25% and a low-level viremia over 5 years ranging between 300-2000 copies. In the 5th year of care he started having recurrent episodes or urinary frequency, urgency, nocturia that required recurrent hospital visits where he was diagnosed with BPH. Despite treatment for his BPH and being under the care of a Urologist JR kept complaining of urinary symptoms, including nocturia, episodes of falling, leg weakness and AMS. With the episodes of AMS he was admitted to the hospital for Urosepsis which was treated with IV antibiotics and had improvement in his urinary symptoms and mild improvement in his AMS. His leg weakness and poor balance remained and so an LP was performed. Results showed CSF HIVRNA of 45,900 while his peripheral HIV RNA PCR was 1600 copies/ml. At this point a diagnosis of HAND was confirmed and he was referred to the neuropsychiatric division of NIH where he was placed in a clinical trial.

CONSIDER….

1. Did the years of low-level viremia put JR at risk for developing HAND?

2. With the diagnosis of HAND would you consider adjusting his ARV regimen to include meds that are at least in category 3 of CPE score?

3. Would you use some form of resistance testing to come up with this alternative ARV regimen?

DIAGNOSTIC CRITERIA

ØNeed to rule out any other etiology of dementia

ØNeed to rule out substance use

ØNeed to rule out any psychiatric illness

THE DIAGNOSIS OF HAD

ØThe diagnosis of HAD includes cognitive deficits in 2 or more cognitive domains that cause impairment in activities of daily living and abnormality in either motor or neurobehavioral function

ØCognitive Domains include:

o Cognition, language, attention, executive function, memory, speed of information processing, perceptual and motor skills

MANAGEMENT/DIAGNOSTIC WORKUP

ØLumbar puncture with CSF analysis

ØNeuroimaging studies (MRI)

ØElectro encephalopathy (EEG)

ØSyphilis serology testing

ØThyroid studies

ØElectrolyte levels

ØDrug screen

ØVitamin B12 & Folic acid levels

MANAGEMENT

ØAggressive highly active antiretroviral therapy

ØFamily education- regarding medication adherence

ØSocial worker/case management assistance –regarding medication adherence and recognizing the early signs and symptoms.

ØAvoid psychoactive drugs: these tend to have a paradoxical effect

CSF ACTIVITY OF ARVS

ØThere is now a score called the CNS Penetration effectiveness score that was designed to classify the current available antiretroviral meds(ARVs) with regards to their capability of lowering CSF RNA levels

ØARVs were assigned a score from 1- 4 based in their chemical properties, CSF penetration, and or effectiveness in prior CNS studies

Ø1 being the lowest and 4 being the highest in terms of CNS penetration and highest in rate of causing CSF RNA viral suppression

CNS PENETRATION- EFFECTIVENESS SCORE

Drug Class 4 3 2 1NRTIs Zidovudine Abacavir

EmtricitabineDidanosineLamivudineStavudine

Tenofovir

NNRTIs Nevirapine DelavirdineEfavirenz

Etravirine

Protease Inhibitors Indinavir Darunavir/rFosamprenavir/rLopinavir/r

AtazanavirAtazanavir/r

NelfinavirRitonavirSaquinavir/rTipranavir/r

Entry/FusionInhibitors

Maraviroc Enfuvirtide

Integrase Inhibitors RaltegravirDolutegravir

Table adapted from Letendre 2011

SUMMARY

KEY POINTS TO KEEP IN MIND:

There is a high prevalence of HAND in ARV treatment naïve patients as well as patients on ART with virologic suppression

HAND is associated with significant cognitive, behavioral & motor abnormalities that can impact ART compliance, retention in care and quality of life

CNS targeted ART should be considered in patients with HAND

Thank YouQ & A

46

TEST YOUR KNOWLEDGEPOST-TEST

TestYour Knowledge Question #1

Which of the following is NOT considered a risk factor for development of HAND?

A. Low CD4 cell nadir

B. Co-infection with hepatitis C

C. The presence of bipolar disorder

D. A past history of pneumocystis jirovecii pneumonia

TestYour Knowledge Question #2

Which regimen is not considered optimal in treating a patient with HAND?

A. Tenofovir-emtricitabine plus dolutegravir

B. Abacavir-lamivudine plus dolutegravir (if HLA-B*5701 is negative)

C. Tenofovir-emtricitabine plus ritonavir-boosted darunavir

D. Tenofovir-emtricitabine plus ritonavir-boosted Tipranavir

TestYour Knowledge Question #3

HIV associated neurocognitive disorders consists of which of the following?

A. Primary CNS lymphoma, Toxoplasmosis, HAD

B. MND, PML, Primary CNS lymphoma

C. ANI, MND, HAD

D. PML, ANI, Primary CNS lymphoma

TestYour Knowledge Question #4

CNS Penetration effectiveness score classifies Anti-retroviral medications into how many categories?

A. 5

B. 4

C. 10

D. 7

REFERENCES

1. https://memory.ucsf.edu/sites/memory.ucsf.edu/files/wysiwyg/UCSF_HIV%20Dementia_Providers_11-6-17.pdf2. https://www.poz.com/basics/hiv-basics/hiv-associated-neurocognitive-disorders-HAND3. https://www.dementia.org.au/sites/default/files/20140723_-_NAT_-_Professional_resources_-_HAND_booklet_for_workers%5b1%5d.pdf4. Case study #1 was adapted from https://www.dementia.org.au/sites/default/files/20140723_-_NAT_-_Professional_resources_-

_HAND_booklet_for_workers%5b1%5d.pdf5. https://www.avert.org/professionals/hiv-around-world/latin-america/overview6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724434/7. https://www.sciencedaily.com/releases/2017/07/170720113652.htm8. https://www.healthycaribbean.org/4th-caribbean-conference-on-alzheimers/9. https://www.caregiver.org/hiv-associated-neurocognitive-disorder-hand10. https://www.infectiousdiseaseadvisor.com/home/decision-support-in-medicine/infectious-diseases/neurologic-disease-in-the-hiv-patient/11. https://www.baptisthealth.com/pages/services/behavioral-health/conditions-we-treat/major-and-mild-neurocognitive-disorder.aspx12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039628/13. Source is ‘Neurological Complications of HIV infections’ by Shelli Farhadia, Payal Patel Curr Infect Dis Rep. December 201714. The original studies showing the new classification presented by Antinori et al in 2007 showing the spectrum/classification of HAND

Howard University HURB 11840 7th Street NW, 2nd Floor

Washington, DC 20001202-865-8146 (Office)202-667-1382 (Fax)

As a Reminder: At the end of the Webinar, All participants are required to complete and return the CME Evaluation Survey. It may be scanned and emailed back to den_bailey@howard.edu, or

faxed to: AETC-Capitol Region Telehealth CenterFAX#: 202.667.1382) ATTN: Project Coordinator

Please indicate in your email or FAX if you would like to receive CMEs.

www.huttc.org