Presentation title times new roman bold 45/48 points

Assessment and
Management of
Psychiatric Issues in
the HIV Positive Patient
Carrie L. Ernst, MD Assistant Professor of Psychiatry Icahn School of Medicine at Mount Sinai March 26, 2014

Disclosure
Author/royalties: American Psychiatric Publishing, Inc Speaker's Bureau (spouse): AstraZeneca Pharmaceuticals

Objectives
• Understand the mechanisms and manifestations of HIV infection of the central nervous system • Describe the clinical presentations and differential diagnoses of HIV associated psychiatric comorbidities • Understand the central role played by psychiatric issues in the assessment, presentation, and management of individuals with HIV • Become familiar with special considerations in the use of standard psychiatric treatment modalities in the HIV-infected population

Epidemiology and Overview
Source: Centers for Disease Control and Prevention. HIV Surveillance Report, 2011; vol. 23. http://www.cdc.gov/hiv/topics/surveillance/resources/reports/. Published February 2013. Stages of HIV Infection
• Stage 1: No AIDS-defining condition + CD4 ≥500 cells/μL or
• Stage 2: No AIDS-defining condition + CD4 200–499 cells/μL or
• Stage 3 (AIDS): AIDS-defining condition or CD4 <200 cells/μL
• Stage unknown: No reported information on AIDS-defining
conditions & no information available on CD4 count or percentage CDC. MMWR 2008;57(RR-10):1–12. HIV Prevalence and Incidence,
1980-2010 in US
Estimated Number of AIDS Cases, Deaths, and
Persons Living with AIDS, 1985-2010: US and
Dependent Areas
1996 introduction Of HAART Source: CDC, 2011 Estimated New HIV Infections in the United
States, 2010
New Diagnoses of HIV Infection among
US Adults and Adolescents by Race/
Ethnicity, 2008-2011
Source: CDC, 2011 Estimated Rate of New HIV
Infections, 2010
New Diagnoses of HIV among Adults and
Adolescents, by Transmission Category,
2008-2011: US and Dependent Areas
Source: CDC, 2011 Estimated New HIV Infections
Among Heterosexuals, 2010, by
Gender and Race/Ethnicity
Proportion of New HIV/AIDS Cases among
US Adults and Adolescents, by Sex and
Transmission Category 2011
Source: CDC, 2011 Percentage of AIDS Classifications among U.S.
Adults and Adolescents with HIV Infection, by
Race/Ethnicity and Year of Diagnosis, 1985-2011
Source: CDC, 2011 Percentage of AIDS Classifications among U.S. Adults
and Adolescents with HIV Infection, by Transmission
Category and Year of Diagnosis, 1985-2011
Why HIV Psychiatry?
Psychiatric issues play a central role in HIV epidemic  HIV as multisystem disease CNS infection  neuropsychiatric symptoms  Psychiatric disorders as vectors of HIV  Psychiatric issues a/w worse outcomes  HIV as chronic illness  Neuropsychiatric side effects of treatment HIV Life Cycle &
Drug Targets
HIV Life Cycle & Drug Targets
Antiretroviral Therapy: 1987
Zidovudine (AZT) Antiretroviral Therapy: 2014
Non- Nucleoside
Protease Inhibitors
Nucleoside Reverse
Reverse Transcriptase
Atazanavir (Reyataz) Delavirdine (Rescriptor) Darunavir (Prezista) Abacavir (Ziagen) Efavirenz (Sustiva) Fosamprenavir (Lexiva) Didanosine (Videx EC) Etravirine (Intelence) Amprenavir (Agenerase) Emtricitabine (Emtriva) Nevirapine (Viramune) Lamivudine (Epivir) Indinavir (Crixivan) Rilpivirine (Edurant) Stavudine (Zerit) Lopinavir/Ritonavir (Kaletra) Tenofovir (Viread) Combination Products
Nelfinavir (Viracept) Tenofovir/Emtrictabine Atripla (efavirenz, Ritonavir (Norvir) emtricitabine, tenofovir) Zidovudine (Retrovir, AZT) Complera (emtricitabine, Saquinavir (Invirase) Lamivudine/Zidovudine rilpivirine, tenofovir) Tipranavir (Aptivus) Stribild (elvitegravir, Abacavir/Lamivudine cobicistat, emtricitabine, Integrase Inhibitors
Raltegravir (Isentress) Entry Inhibitors
Fusion Inhibitors
Dolutegravir (Tivicay) Maraviroc (Selzentry) Enfuvirtide (Fuzeon) Elvitegravir (part of Stribild) Arts and Hazuda, Cold Spring Harb Perspect Med 2012;2 HIV Infection of the
Central Nervous System
HIV Infection of the CNS
 HIV invades CNS within hours to days via infected monocytes (differentiate into macrophages)  Cell free virus also enters CNS by infecting endothelial cells of blood brain barrier  Infected macrophages infect other cells in CNS by direct contact  Neurons are not directly infected  Get further CNS viral replication in microglia and macrophages  Direct & indirect neuronal damage occurs – Virally infected cells secrete neurotoxic inflammatory substances – Viral particles/proteins are directly neurotoxic  HIV prefers subcortical structures- 1st basal ganglia  CNS is independent reservoir of HIV replication Model of HIV-related Neuronal
Damage
Kaul et al, Nature 410: 988-994, 2001 Neuropsychiatric Syndromes:
HIV-Associated Neurocognitive
Disorder (HAND)
 HIV-associated dementa (HAD)
– Acquired impairment in ≥2 cognitive domains – >2 SD from age-adjusted population norms – Caused by HIV – Marked impairment in ADLs  Mild neurocognitive disorder (MND)
– Similar to HAD except ≥1 SD from population norms with some impairment in ADLs  Asymptomatic neurocognitive impairment (ANI)
– Same neurocognitive impairment as MND but no impairment in ADLs Neuropsychiatric Syndromes:
HIV Associated Dementia (HAD)
Motor Cognitive Unsteady gait/loss of balance Poor visuospatial memory Poor visuomotor coordination Poor complex sequencing Tremors/poor handwriting Impaired attention/concentration Poor fine motor skills Impaired verbal memory Affective Behavioral Apathy Psychomotor slowing Mania, new psychosis Personality change Social withdrawal Risk factor for suicide Epidemiology of HAND
 Pre-HAART: up to 40% prevalence of  Post-HAART: HAD uncommon but milder neurocognitive impairment common; 20-85% prevalence  CHARTER Study1 – HAD: 2% – MND: 25% – Any HAND diagnosis: 50% 1. Heaton et al, Neurology 2010; 75:2087-2096 Risk Factors for HAND
• Low current CD4 count • Nadir CD4 count • High plasma or CSF viral load • Anemia (?) • Co-infection with Hepatitis C • Extremes of age • IVDU • Metabolic & Cardiovascular factors Rackstraw. Psychology, Health & Medicine, 16:5, 548-563, 2011 Screening for HAND
 Assess neurocognitive function early in all HIV patients  Screen every 6-12 months if higher-risk patients, every 12-24 months in lower-risk patients  Screen immediately if evidence of clinical deterioration or major change in clinical status  Many proposed brief screens  Neuropsychological testing if available or for selected patients  Use screens with clinical information & risk profiles  Assess adherence  Psychosocial history + functional assessment HIV Dementia Scale
Brief but sensitive screening instrument (sensitivity 80%, specificity 91%, PPD 78%) (6) Psychomotor speed (timed written alphabet) (4) Memory (recall of 4 words at 5 minutes) (4) Attention (antisaccadic eye movements) (2) Construction (timed cube copy) Score ≤ 10 indicates possible HAD Power et al. J AIDS 1995; 8:273–278. Work-up for the HIV patient with
Neurocognitive Impairment
 Thorough medical and neurological history  Developmental history  Substance use- past and present  Psychiatric assessment (depression, anxiety, PTSD)  Neurological examination  Laboratory studies: CD4 cell count, HIV RNA, RPR, HCV Antibody, TSH, testosterone profile, metabolic panel, hepatic function tests, B12, folate  CSF Analysis Modified from The Mind Exchange Working Group;CID 2013:56 HIV Dementia: Neuroimaging
MRI-T2 MRI-FLAIR Management of HAND
 Combination ARV therapy  Assess and improve adherence to ARVs  Must decide if brain penetration is a crucial component in the design of future HIV therapy  Treat co-morbidities (Hepatitis C, cardiovascular risk factors)  Monitor frequently, especially if higher risk Management of HIV Dementia:
Antiretrovirals and CNS penetration
Increasing CNS Penetration nRTIs Didanosine Emtricitabine Abacavir Tenofovir Lamivudine Zidovudine Adefovir Stavudine NNRTIs Efavirenz Delavirdine Nevirapine PIs Nelfinavir Atazanavir Amprenavir/r Ritonavir Fosamprenavir Fosamprenavir/r Saquinavir Indinavir Indinavir/r Saquinavir/r Atazanavir/r Lopinavir/r Tipranavir/r Darunavir Other Enfuvirtide Raltegravir Maraviroc Elvitegravir Adapted from Smurzynski et al AIDS. 2011 January 28; 25(3): 357–365. Management of HAND: Adjunctive
Pharmacological Treatment
 Minocycline
 Cholinesterase inhibitors  Valproic Acid  Psychostimulants Management of HIV Dementia:
Non-pharmacological
 Simplify complex tasks (ex- drug regimens)  Use pill boxes, diaries, timers  Repeat information  Write out instructions  Educate caregivers and patients  Maintain orientation cues  Keep environment familiar  Structured routines and activities  Cognitive stimulation Additional CNS Complications
Accompanying HIV Infection
 Infectious: CMV, syphilis, HSV, TB, toxoplasmosis, progressive multifocal leukoencephalopathy (PML), fungal  Oncological: Lymphoma, metastatic disease  Endocrine/Nutritional: thyroid, addison's, B12 deficiency, anemia  Drug intoxication or withdrawal  Antiretroviral medications and drug-drug HIV-Associated
Psychiatric
Comorbidities
HIV and Psychiatric Illness: HIV Cost
and Services Utilization Study
• Nationally representative probability sample of HIV- infected adults receiving medical care in US • Screened for symptoms of MDD, dysthymia, GAD, panic attacks, and illicit drug use and dependence within the past year • 77.4% male, 49.2% white, 40.4% heterosexual Bing et al, Arch Gen Psychiatry 2001; 58:721-728 HIV Cost and Services Utilization
Study: Results
NCS-R
(N= 9282)
1. Bing et al, Arch Gen Psychiatry 2001; 58:721-728 2. Kessler et al, Arch Gen Psychiatry 2005; 62:617-627 HIV Cost and Services Utilization
Study: Results
Risk factors associated with screening positive for a
psychiatric disorder: • Age < 35 years • Caucasian • Living alone or with non-partner • Unemployed or disabled • Greater # of HIV-related symptoms • Illicit drug use or dependence (excluding marijuana) • Heavy alcohol use Bing et al, Arch Gen Psychiatry 2001; 58:721-728 AIDS Healthcare Foundation
Retrospective Cohort Study
• N = 7834 HIV-positive patients receiving treatment in
ambulatory care clinics in California • Any psychiatric condition: 53% • Any mood-related disorder: 23% • Any anxiety-related disorder: 16% • Any substance-related disorder: 19% Parhami et al, AIDS Behav 2012 Depression and HIV
• Most common psychiatric manifestation associated with • Prevalence: 18-81% • HCSUS: 36% MDD, 26.5% dysthymia1 • HCSUS re-estimation of data: 22% MDD, 5% dysthymia2 • Meta-analysis: 2x increased risk MDD in HIV pts3 • HIV+ women > men • ↑ risk if advanced disease, hx MDD, psychosocial stressors • Atypical features • Associated with poor ARV adherence and worse outcomes Bing et al, Arch Gen Psychiatry 2001; 58: 721-7281 Orlando et al, Int J Methods Psychiatr Res 2002; 11: 75-82 Ciesla and Roberts, Am J Psychiatry 2001; 158: 725-730 Depression and HIV
Demoralization, Stigma, Isolation Debility, disability Depression
Cognitive Impairment Direct cortical & subcortical injury Pro-inflammatory cytokines Cognitive Impairment HIV/AIDS
Faster disease progression ↓ # and activity of NK & CD4 cells HIV-Related Mortality in
Depressed Women
HIV Epidemiology Research Study (n= 765) (log-rank test: P<.001) Ickovics et al, JAMA 2001; 285:1466-1474 Mania and HIV
• Prevalence: 1-2% in HIV, 4-8% in AIDS • Associated with CD4+ < 100, HAD, MCMD • Unique Features of HIV-associated mania: Irritability > Euphoria No history mood disorder Chronic > Episodic Higher rates of HAD Later age of onset No family history Increased talkativeness Mania and HIV
Increased stress Direct CNS effects (cytokines, caudate) Impulsivity/Risk Behaviors HIV/AIDS
Cognitive Impairment Anxiety Disorders & HIV
• Prevalence: 10-72% • HCSUS: 15.8% GAD, 10.5% panic disorder • Increase with illness progression • Pre-existing anxiety disorders exacerbated • Associated with: ↓ Adherence, ↑ Risk behaviors and ↑ Substance abuse • May affect immune function • PTSD a/w ↓CD4+, CD4+/CD8+, & NK cells • ↑ Cortisol  ↓immune function • PTSD a/w disturbed regulation of HPA axis & sympathoadrenomedullary system Death/Dying preparation Milestones Functional disability Initiation of ARVs Disclosure of HIV status Onset AIDS-defining illness ↓ CD4 counts/↑viral load Appearance of 1st illness symptoms News of HIV positive status Psychotic Disorders and HIV
• Can be primary or secondary • HIV prevalence among people with serious mental illness is greater than that of the general population • 2001 data: 3.1% prevalence (8x greater than general • Schizophrenia is a risk factor for HIV • Poor adherence • Many barriers to medical care • Longer medical hospitalizations • ↑ suicidality • May decompensate upon diagnosis • More sensitive to extrapyramidal side effects of 1. Rosenberg et al. Am J Public Health 2001; 91:31-37 Substance Abuse and HIV
• Substance abuse ↑ risk for HIV transmission • HIV Cost & Service Utilization Study: 50% of HIV+ individuals reported drug use in past 12 mo Bing et al, Arch Gen Psychiatry 2001; 58:721-728 Substance Abuse and HIV
• Poor adherence • Less likely to access HAART • Diagnosed at more advanced stage • More opportunistic Infections • High risk sexual and injection behaviors • Interactions with HAART • ↑ risk cognitive impairment/dementia Substance Abuse & HIV: Effects on
Immune Function
• Cocaine: augments HIV replication,↑
permeability of BBB to HIV • Alcohol: immunosuppressive; enhances HIV
infection of lymphocytes • Opioids: ↑ ability of HIV to infect target cells;
Morphine inhibits CD8+ T-cell-mediated anti-HIV activity in latently infected immune cells • Methamphetamine: may ↑ viral replication and
Additional Psychiatric Issues
Associated with HIV
Psychodynamic Themes
• Suffering as sign of weakness in face of adversity • Guilt over getting HIV • Guilt over infecting others • Anger at source of disease, oneself, God • Precipitous revelation of hidden sexual or drug abuse behavior  shame and self loathing • Stigma leading to rejection or abandonment by others, feel like lepers • Some become hopeless and nihilistic and refuse tx How Would You Differentiate Between Primary and
Secondary Psychiatric Disorders?
Secondary
• Personal history of similar • No personal or family psych hx • More chronic • Family psychiatric history • Neuro-cognitive deficits • Fluctuating consciousness • Neuro-cognitive symptoms rare • Evidence of organ dysfunction • Typical features • Prominent neurovegetative • Uniquely psychiatric symptoms (ex- hopelessness, helplessess, • Personality change worthlessness, apathy) • Temporal association • Atypical Features • Age of onset >40 • Abnormal vital signs • Lower CD4 counts & higher VLs Differential Diagnosis of Psychiatric Symptoms
in HIV Patients
• Direct CNS manifestation of HIV • CNS infections & malignancies • Endocrine/Metabolic disturbances • HAND • Vitamin Deficiencies • Drug intoxication or withdrawal • Cardiovascular or pulmonary disease • Medications Neuropsychiatric Side Effects of
ARVs
• Efavirenz: 50% develop neuropsychiatric sx
Dizziness, headache, ↓concentration, confusion, insomnia,
nightmares, anxiety, amnesia, depersonalization, euphoria, depression, hallucinations, SI • NRTIs:
Didanosine: anxiety, insomnia, seizures, confusion
Lamivudine: insomnia, mania
Stavudine: h/a, malaise, depression, mania, insomnia,
Zidovudine: h/a, malaise, insomnia, vivid dreams, AH
agitation, mania, confusion, depression Management of
Psychiatric Disorders
in HIV patients
Effects of Mental Health
Interventions for HIV Patients
• Improved ARV adherence • Increased CD4 cell count • Decreased risky sexual behaviors • Decreased suicidality • Improved quality of life • Decreased medical complications • Improved prognosis (?) iewed by Arseniou et al. Psychiatry and Clinical Neurosciences 2014; 68:96-109 Springer et al. AIDS Care 2009; 21:976-983 Pharmacological Considerations
for HIV Patients
• Psychotropic-ARV interactions • Substrates, inducers, inhibitors of multiple CYP450 isoenzymes • Ritonavir is CYP3A4 & CYP2D6 inhibitor • CYP3A4 substrates & inducers • CYP2C9 & 2C19 inhibitors • Most psychotropics: CYP 2D6 & 3A4 substrates and/or inhibitors • Increased or atypical adverse effects • Neuropsychiatric side effects of ARVs • Adherence (pill burden, cognitive deficits) Reviewed by Gallego et al, AIDS Rev 2012; 14:101-11 Treatment of MDD Associated with
HIV: Antidepressant Efficacy
(paroxetine vs imipramine) Himelhoch and Medoff, AIDS Patient Care STDS, 2005; 19: 813-822 Psychotropic-HAART
Interactions: Antidepressants
NNRTIs Fluoxetine and Efavirenz may ↑ buproprion fluvoxamine may ↑ NNRTIs (3A4, 2D6) St. John's Wort may ↓ Nevirapine may ↓ fluoxetine (3A4) Most SSRIs may ↑ PIs may ↑ trazodone, duloxetine, venlafaxine, PIs may ↑ most mirtazapine, modafinil, & stimulants (3A4, 2D6) Potential for Ritonavir may ↑ buproprion serotonin syndrome St. John's Wort ↓ PIs (3A4) Novel Antidepressants
• Psychostimulants: may help depression +
• Testosterone: potential benefits for depressive
symptoms and fatigue in hypogonadal patients with AIDS wasting • DHEA: may help milder forms of depression
• Modafanil/Armodafinil: Open- label & RCT data
for fatigue in HIV patients Additional Effects of
Antidepressants in HIV patients

• Improved pain control (SNRIs)
• Improved sleep (mirtazapine)
• Improved appetite/weight (mirtazapine,
• Improved energy (stimulants, modafinil, • Decreased nausea (mirtazapine) Psychotherapy for Depression in
HIV patients
• Interpersonal psychotherapy • Cognitive behavioral therapy • Cognitive behavioral stress management group • Brief supportive psychotherapy Use of Antipsychotics in HIV
Patients
• Appear to be efficacious but not well studied • More sensitive to extrapyramidal side effects • PIs may ↑ typical antipsychotics, aripiprazole, quetiapine, risperidone, ziprasidone (3A4, 2D6) • Pimozide contraindicated with PIs (cardiac) • PIs may ↓ olanzapine (1A2) • In late stage infection, start low, go slow • Overlapping metabolic effects • Bone marrow toxicity with Clozapine and Zidovudine Use of Mood Stabilizers in HIV
Patients
• Additive renal toxicity from lithium + tenofovir • Lithium may improve neuropsychological function • Data suggesting valproate increases HIV replication in vitro (but not found in vivo) • Hepatoxicity from valproate • Lamotrigine effective in HIV-associated neuropathic pain • Avoid Carbamazepine Psychotropic-HAART
Interactions: Mood Stabilizers
Valproate
Carbamazepine Other AEDs
Oxcarbazepine
Valproate may ↑ zidovudine (gluc) PIs may ↓ valproate CBZ ↓ PIs (3A4) PIs may ↓ lamotrigine PIs ↑ CBZ (3A4) (gluc) CBZ ↓ maraviroc Use of Sedative/hypnotics in HIV
Patients
HIV patients more sensitive to side effects Limited data examining benzodiazepine efficacy for anxiety treatment in HIV Most sedative/hypnotics have extensive CYP3A4 metabolism Decreased benzodiazepine and non-benzodiazepine hypnotic clearance when administered with PI Midazolam & triazolam contraindicated with PI or efavirenz Lorazepam, clonazepam preferable Helpful Resources for Drug-Drug
Interactions

Other Aspects of Psychiatric Care
for HIV Patients
• Therapeutic relationship
• Care coordination • Treatment adherence • Health education • Prevention of high risk behaviors • Coping with disability and chronic illness • Work with families, friends and partners • Integration of religion and/or spirituality • Expanding support network Conclusions
 Among new HIV/AIDS cases, an increasing percentage comes from unprotected heterosexual activity and higher-risk demographic groups  Common neuropsychiatric syndromes associated with HIV include cognitive dysfunction, depression, psychosis, substance abuse and suicidality  All HIV patients should be screened for cognitive dysfunction, regardless of virologic control  Sexual and drug use histories should be incorporated into routine psychiatric evaluations and HIV testing should be considered as appropriate Conclusions (continued)
 Traditional psychotropic medications are effective but require closer monitoring due to higher risk for adverse effects and drug-drug interactions  Antiretrovirals carry risk of neuropsychiatric side effects and risk/benefit analyses are important  Medical, psychiatric and substance use treatment services should be integrated with efforts directed at improving access to care  Skill-based risk reduction strategies designed for the seriously mentally ill and cognitive impaired should be considered

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