Human Immunodeficiency Virus (HIV)

Clinical Presentation

MOOD DISTURBANCES

• Major depression: seen in about 20% of HIV patients presenting for medical treatment
  • Symptoms: depressed mood, loss of pleasure from activities, anorexia, morning insomnia or hypersomnia, difficulty concentrating, thoughts of suicide
  • Treatment: antidepressants, starting with low doses and titrating slowly:
    • The mainstay of treatment has been SSRI and SNRI antidepressants, although other antidepressants seem to be effective as well.
    • Tricyclic antidepressants (TCAs) may be beneficial in individuals with chronic pain, stomach distress, chronic diarrhea, and depression due to anticholinergic actions.
      • Levels need close monitoring when these drugs are used because of a narrow margin of safety.
• Demoralization (adjustment disorder): seen in about 20% of HIV patients presenting for medical treatment
  • Symptoms: grief, sadness, hopelessness, often precipitated by life circumstances
    • Unlike depression, patients often can enjoy some facets of life and feel best in the mornings.
  • Treatment: psychotherapy and support
• Bipolar disorder: seen in about 9% of hospitalized AIDS patients and in about 3% of HIV patients presenting for medical treatment
  • Symptoms: manic episodes, depressive episodes, and mixed episodes
  • Treatment: For AIDS-related mania, acute management includes antiretroviral therapy (ART)
    • In addition, mood stabilizers such as valproic acid and other anticonvulsants are used, as well as neuroleptics
    • Mania associated with advanced HIV infection (previously "AIDS mania"): A syndrome occurring in late stage of HIV infection that has been associated with HIV dementia and rapid deterioration. Uncommon in the ART era.
      • Treatment is ART and low-dose neuroleptics to stabilize behavior.
• Anxiety: a common symptomatic complaint
  • Generalized anxiety disorder shows an 8-fold increase over background, but poor discrimination for specific diagnosis.
  • Panic attacks show a 4-fold increase over background
    • Panic attacks: characterized by recurring anxiety attacks with fear plus somatic symptoms of excitation lasting < 1 hour
    • Treatment is often an SSRI with management by a psychiatrist.

DELIRIUM

• Reported in 12-29% of HIV-infected patients throughout course of illness
• Symptoms: waxing and waning symptoms and level of consciousness, inability to attend, global derangement of brain function, disorganized thinking, may have hallucinations, delusions, paranoid or other psychotic symptoms
• Treatment: correct underlying condition, which is usually multifactorial
  • Minimize anticholinergic drugs, improve orientation and stimulation including improved day-night cues and cycles, and correct medical conditions.
  • Always consider occult sepsis or abscess.
  • For agitation, lowest useful dose of neuroleptics

COGNITIVE DISTURBANCES

• The HIV-associated neurocognitive disorders (HAND) that result from HIV infection have historically shown a "subcortical pattern" with prominently impaired executive function, slowing of processing speed, problems with more demanding attentional tasks, difficulty in learning new information, and subtle motor difficulty.
  • Unlike those with some other dementias, these individuals show fewer problems with recall of learned information.
  • This pattern has changed with an aging HIV population and ART to include more cortical deficits, resulting in a more mixed picture of deficits.
  • Severe neurocognitive disease is less common in the era of ART
• Although it varies by stage of disease, one-third to one-half of HIV-infected individuals have at least mild neurocognitive disorders[4].
  
  • 25% of individuals with HIV will have signs and symptoms that meet criteria for mild neurocognitive disorder.
  • 5% of individuals with HIV will have signs and symptoms that meet criteria for major neurocognitive disorder.
  • Neurocognitive disorder due to HIV infection has not declined significantly with the advent of combined ART, although the most severe presentations have decreased sharply.
• More prevalent in individuals with prior episodes of severe immunosuppression, high viral loads in the cerebrospinal fluid (CSF), and indicators of advanced HIV disease.
• In most severe cases, may see neuromotor features such as severe incoordination, ataxias, and motor slowing.

SUBSTANCE-USE DISORDER

• Concern arises when there is use of substances despite clear evidence of negative consequences.
• Dependence: persistent use or seeking use, withdrawal, tolerance, and physical dependence
• As in other individuals, those infected with HIV benefit from methadone or buprenorphine treatment for opiate dependence.

Tests and Procedures

• Screening: use fourth-generation antigen/antibody tests (which detect p24 antigen and antibodies) as first-line; Western blot is no longer recommended for confirmation.[5]
  • If screening is positive, follow with HIV-1 / HIV-2 differentiation assay, and for acute or ambiguous cases, HIV RNA (PCR) testing.[5]
• CSF analysis may be helpful if it shows a disproportionately high viral load in CSF vs. the plasma, as well as for ruling out CNS opportunistic infections (such as tuberculosis, cryptococcal meningitis, syphilis, and cytomegalovirus).
• Neuroimaging (in particular MRI) is useful in patients with advanced disease to rule out AIDS-related illnesses.
  • e.g. opportunistic infections such as toxoplasmosis or cryptococcus
  • e.g. CNS malignancy such as lymphoma
  • Neuroimaging may also show reduction in total brain volume, cortical thinning, reduction in white matter volume, and patchy areas of abnormal white matter (hyperintensities)[1].

Differential Diagnosis

• Infection: e.g., opportunistic infections of the brain (toxoplasmosis, cryptococcus)
• Deficiencies: e.g., vitamins B₆, B₁₂, A; zinc
• Endocrine disorder: e.g., thyroid disease, adrenal insufficiency, hypogonadism
• Neoplasia: e.g., CNS lymphoma
• Medication adverse reactions: e.g., efavirenz, corticosteroids, interferon
• Substance misuse
• If cognitive impairment, other neurodegenerative disorder: e.g., Alzheimer disease

General

• Treatment is recommended for all persons with HIV, regardless of CD4+ count or clinical stage, as soon as diagnosis is confirmed. Delaying ART is no longer standard practice.
• Public health interventions are crucial to: (1) maximize ART adherence so individuals maintain undetectable viral load to avoid sexual transmission; and (2) prevent infection via condom use, pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), and regular screening.
• Ideally, treatment of HIV-infected individuals takes place within a multidisciplinary team with an infectious disease physician, a psychiatrist, social workers, case managers, and nursing staff.

Pharmacotherapy

• Preferred initial regimens in adults/adolescents include integrase strand transfer inhibitors (INSTIs) (e.g., dolutegravir, bictegravir, raltegravir) combined with two nucleoside reverse transcriptase inhibitors (NRTIs). These combinations tend to avoid most drug-drug interactions. Older first-line agents such as nevirapine, efavirenz, zidovudine, delavirdine are now rarely used except in special situations.[6][7]
  • Most INSTIs have minimal or no CYP450 interactions. Elvitegravir has CYP450 interactions because it’s co-administered with cobicistat/ritonavir. Dolutegravir/bictegravir have minor CYP3A involvement.[8]
  • All protease inhibitors and nonnucleoside (or nucleotide) reverse-transcriptase inhibitors (NNRTIs) are metabolized by the cytochrome P450 system and possess enzyme-inhibiting or enzyme-inducing properties.
    • Ritonavir (metabolized by CYP3A4 and 2D6) may be associated with the most significant interactions because of its potent inhibition of CYP3A, 2D6, 2C9, and 2C19 isoenzymes.
    • Amprenavir, indinavir, and nelfinavir are all metabolized by CYP3A4 and are moderately potent CYP3A4 inhibitors.
  • The nucleoside reverse-transcriptase inhibitors (NRTIs) have fewer theoretical P450 interactions, making them less vulnerable to interactions with psychotropic medications.
• Drug-drug interaction monitoring is vitally important, especially since individuals with HIV are often on multidrug regimens[9]. It is not clear how often psychotropics adversely impact antiretroviral blood levels (causing either toxicity or failure).
• Please review the drug modules of the guide for detailed information on how each drug class affects the cytochrome P450 system. In brief:
  • All SSRIs may potentially interact leading to a potential for increased levels of SSRI when used in combination with P450 inhibitors.
  • Trazodone, often used as an adjunctive sleeping agent, may show increased levels when combined with P450 inhibitors.
  • Bupropion levels may be increased when used with P450 inhibitors; studies have not shown an increase in the number of seizures.
  • TCAs when combined with P450 inhibitors increase TCA levels; close monitoring for symptoms of TCA toxicity are important.
  • Of the benzodiazepines, alprazolam, midazolam, and triazolam are dependent on P450 metabolism, and potent inhibitors, such as ritonavir, can decrease clearance of these drugs and result in oversedation and possibly death.
    • Oxazepam, lorazepam, and temazepam are metabolized by glucuronidation, and ART that increases the activity of glucuronidation, such as dolutegravir, raltegravir, ritonavir, or nelfinavir, may lower the levels of these drugs.
  • Valproic acid does not appear to exhibit significant P450-based drug interactions with ARTs.
  • Concentration of neuroleptics may be increased by ARTs with P450 inhibition.

Psychotherapy

• Supportive psychotherapy, whether informal or formal, has a role for all HIV-infected patients.
• Cognitive behavioral therapy (CBT) may be a useful method for helping patients with medication adherence.