HIV Virus

Medications and Infectious Diseases

Table of Contents

Overview

Human behavior (mobility, travel, sexual practices, substance use, treatment adherence) has a very complex relationship with infectious diseases when it comes to infection risk and treatment outcomes. Psychiatric symptoms are part of the clinical presentation of many systemic and central nervous system infectious processes such as HIV/AIDS, Cysticercosis, Syphilis, Toxoplasmosis, and West Nile Encephalitis. Infectious diseases have been implicated in the pathogenesis of many psychiatric disorders (viral hypothesis of Schizophrenia, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections/PANDAS, and Lyme disease). 

Preexisting neurological diseases such as traumatic brain injury, neurodegenerative disorders, neurocognitive disorders, and advanced age render patients more vulnerable to the neuropsychiatric effects of both the infection itself and antimicrobials. A simple upper respiratory infection or urinary tract infection in a young healthy individual is less likely to present with signs of confusion, disorientation, and inattention (i.e., delirium). These signs and symptoms are relatively common in elderly patients with history of multiple cerebrovascular accidents (CVAs) or Alzheimer’s-type dementia. The reasons for this are unknown but are thought to be related to permeability changes in the blood brain barrier and the effects of inflammatory mediators (cytokines, hormones, etc.).

 

An acute change in neuropsychiatric symptoms may be the first sign of impending sepsis and may even precede the development of fever!

It is worth mentioning that psychological factors significantly affect the risk for, and the course of, infectious diseases. In a large cohort of patients hospitalized for infection, 30 day mortality rate was 52% higher for those with history of severe mental illness than those without (Ribe et al. 2015).

 

Neuropsychiatric Effects of Antimicrobial Drugs

DRUG CLASSNeuropsychiatric Adverse Effects
Antibacterials
CephalosporinsEuphoria, delusions, depersonalization, illusions
DapsoneInsomnia, agitation, hallucinations, mania, depression
Procaine PenicillinAgitation, depersonalization, hallucinations, Fear
QuinolonesPsychosis, Paranoia, Mania, Agitation, Tourette’s Sxs
TMP-SMXDelirium, psychosis
GentamicinDelirium, psychosis
ClarithromycinDelirium, mania
Antituberculous
CycloserineAgitation, depression, psychosis, anxiety
IsoniazidPsychosis, Mania, Agitation, depersonalization
EthionamideDepression, hallucinations
Antivirals
Acyclovir, ganciclovirPsychosis, delirium, depression, anxiety
AmantadinePsychosis, delirium
Oseltamivir, zanamivirPsychosis, delirium
Interferon-alfaIrritability, depression, agitation, paranoia
Interleukin-2Psychosis, delirium
Antifungals
AmphotericinDelirium, psychosis, depression
Antiparasitic
AntimalarialsConfusion, delirium, psychosis, mania, depression, anxiety, aggression
Metronidazole*Depression, delirium, Disulfiram-like reaction
Thiabendazole Psychosis

 

Drug-Drug Interactions

Drug-drug interactions can be divided into pharmacokinetic interactions and pharmacodynamic interactions. Drug interactions between antimicrobials and psychotropic medications most often occur due to two types of pharmacokinetic interactions described briefly below. While only two types of common interactions are described below, it is important to appreciate that others exist and are relevant as well.

  • Protein Binding: Most drugs are transported in the blood by plasma proteins (e.g. albumin). Typically an equilibrium exists between freely floating drug and protein-bound drug. In order for a drug to be effective, it must detach from the plasma protein to reach its target. This means that the bioactive form of most drugs are the freely floating portion in blood. Some drugs compete for binding sites on the plasma proteins and may displace a protein-bound drug which will increase the freely floating portion of the displaced drug. This will raise free drug levels in plasma and increase the risk of adverse/toxic effects. Luckily, freely floating drugs are also available for elimination, which usually decreases the risk of toxicity (assuming organs of elimination are functioning properly).   
  • CYP450 System: The CYP450 enzymes are in almost all cells of the body with higher concentrations in hepatocytes, intestinal mucosal epithelium, and kidneys. CYP450 enzymes are responsible for metabolizing most medications used in medicine. The isozymes CYP450 3A4 and 2D6 account for the majority of metabolism of drugs in humans. Drugs that inhibit or induce the activity of these CYP450 enzymes often cause clinically significant drug interactions.

 

Important Antimicrobial-Psychotropic Drug Interactions

  • Antimalarials: Increase phenothiazine (e.g. chlorpromazine) levels
  • Azoles: Increase alprazolam, midazolam, and buspirone levels
  • Clarithromycin, Erythromycin: Increase alprazolam, midazolam, carbamazepine, clozapine, and buspirone levels
  • Quinolones: Increase clozapine and benzodiazepine levels but decreases benzodiazepine effects
  • Isoniazid: Increases haloperidol and carbamazepine levels. Isoniazid + disulfiram can cause ataxia
  • Linezolid: Serotonin syndrome if used with serotonergic drugs
  • Erythromycin, Clarithromycin, and Ketoconazole: QT prolongation and ventricular arrythmias with TCAs and antipsychotics
  • Linezolid is an irreversible MAO-A inhibitor: Serotonin syndrome and Hypertensive crisis
  • Isoniazid is a weaker MAO inhibitor: Reports of Serotonin syndrome and hypertensive crisis

 

 

Human Immunodeficiency Virus (HIV)

Human Immunodeficiency Virus (HIV). From Robbins and Cotran Pathologic Basis of Disease. 8th Edition. 2010. 

Human Immunodeficiency Virus (HIV) is a retrovirus and contains two viral RNA molecules, an enzyme called reverse transcriptase, and accessory proteins

HIV infects human white blood cells via the following steps:

The virus binds to the surface of CD4+ cells via another cell surface protein (CCR5)

The virus is internalized within human cells

The virus uses the deoxynucleotides present in human cells to reverse-transcribe its RNA into DNA by the viral enzyme reverse transcriptase

The newly formed DNA strands are translocated into the human cell’s nucleus and is integrated into the DNA by the viral enzyme integrase

The activated cell with virally derived DNA then produces a large number of viral RNA strands

The cell’s own machinery is used to make these viral proteins

Finally, the viral protease cleaves the proteins and allows the mature viral particles to leave the cell

Drugs used in the prevention and treatment of HIV interfere with one or more of the above steps:

Fusion inhibitors: interfere with viral entry

Reverse transcriptase inhibitors (both nucleoside and nonnucleoside reverse transcriptase inhibitors): interfere with reverse transcription of viral RNA into DNA

Integrase inhibitors: Interfere with the integration of virally-derived DNA into the host cell genome

Protease inhibitors: interferes with the activity of viral proteases that cleave proteins and allow maturation and release of viral particles

Successful treatment involves the use of a combination of multiple drugs (antiretroviral therapy, ART) to achieve undetectable viral levels and prolong life for HIV infected individuals

Fun Statistics

  • Approximately 37 million people worldwide are living with HIV infection
  • 1.2 million people in the US are living with HIV
  • Approximately 1 in 8 individuals are not aware of their infection
  • 6% of new infections attributed to IV drug use (likely even higher)
  • Over 80% of new infections in the United States are among Men who have sex with men (MSM)
  • Among MSM, men with four to five co-occurring conditions had more than eight times the hazard of HIV infection compared with those with no such conditions
  • African Americans are at greatest risk – African Americans represent 12% of US population but account for approx. 45% of HIV cases.
  • In the US, the prevalence of HIV is substantially higher among adults with serious mental illness (SMI)
  • Mental health disorders and HIV acquisition have a complex relationship (Mental Health disorders increasing the risk of HIV acquisition by up to 10 fold)
  • Some evidence suggests a linear relationship between severity of mental illness and rates of HIV infection
  • The number one reason for HIV treatment failure is nonadherence to medication treatment
  • Research has established links between the presence of psychiatric illness, especially substance use disorders, and poor rates of HIV care linkage and retention
  • Research has clearly identified depression as one of the strongest predictors of poor antiretroviral medication adherence across the entire socioeconomic spectrum

Depression and HIV/AIDS: A Biological Model

There is evidence suggesting a bi-directional relationship between depression and the immune system.

HIV and the resulting chronic immune activation increase the risk to develop mental health problems.

 

 

Psychopharmacology in Patients with HIV/AIDS

General Guidelines for prescription of psychotropic medication to HIV patients:

  1. Start at lower doses and increase gradually based on tolerability and response
  2. Use the simplest possible regimen
  3. Use drugs with a side effect profile that can be used as a therapeutic advantage
  4. Consider drug pharmacokinetics to minimize interactions

 

  • Patients at advanced stages of liver or HIV disease have physical and cognitive impairment that increase sensitivity to side effects
  • Prolonged use of antiretroviral medications may lead to metabolic syndrome and increased risk for cardiovascular/cerebrovascular diseases
  • Psychotropics that induce similar metabolic changes should be avoided, if possible (Examples: Olanzapine, Clozapine, Quetiapine, Valproate)
  • Patients with a current or past history of substance dependence have greater risk of abuse of many psychotropic drugs: Quetiapine (“Suzie Qs”), Gabapentin, Bupropion (snorted), Benzodiazepines
  • HIV patients have alterations in brain neurotransmitter systems (DA, 5HT) which may explain the atypical course and unpredictable responses to psychiatric medications

 

Drug-Drug Interactions

  • NRTIs are predominantly excreted at the kidney
  • Minimal interactions with psychotropics
  • NNRTIs have extensive metabolism via CYP450 (e.g., Nevirapine, Efavirenz and Etravirine are Substrates and inducers of CYP3A4 and Efavirenz and Etravirine inhibit CYP2C9 and CYP2C19)
  • Protease Inhibitors also have extensive metabolism via CYP450
  • Ritonavir is most potent inhibitor of CYP3A4 and CYP2D6
  • CCR5 Blocker Maraviroc is metabolized by CYP3A4 but is not an inducer or inhibitor of CYP3A4
  • Fusion inhibitor enfuvirtide (cleared by kidney) and the integrase inhibitor raltegravir (cleared via glucuronidation) have minimal to no clinically significant interactions with psychotropics

 

Neuropsychiatric Effects of Antiretroviral Medications

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)Neuropsychiatric Side Effects
AbacavirDepression, Mania, Suicidal ideation, Anxiety
Psychosis, Insomnia, Nightmares, Fatigue
DidanosineNervousness, Agitation, Mania, Lethargy
EmtricitabineDepression, Odd dreams, Insomnia, Confusion, Irritability
Interferon-a-2aDepression, Suicidal ideation, anxiety, mania, psychosis, insomnia, delirium, altered cognition
LamivudineDepression, Insomnia, Dizziness, dystonia
ZidovudineAnxiety, Agitation, Restlessness, Insomnia, Mania, Psychosis
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
DelavirdineAnxiety, Agitation, Amnesia,
Lightheadedness/dizziness
EfavirenzAnxiety, Insomnia, Irritability, Depression
Suicidal ideation, psychosis, Nightmares, Vivid dreams
Lightheadedness/dizziness
NevirapineVivid dreams, Nightmares, Visual hallucinations
Delusions, Mood Instability
Lightheadedness/dizziness
EtravirineInsomnia, lightheadedness/dizziness
RilpivirineOdd Dreams, Insomnia, lightheadedness/dizziness
Protease Inhibitors
AtazanavirDepression, Insomnia
FosamprenavirDepression
IndinavirAnxiety, Agitation, Insomnia
Lopinavir and RitonavirInsomnia
NelfinavirDepression, Anxiety, Insomnia
RitonavirAnxiety, Agitation, Euphoria
Hallucinations, Taste changes
Decreased libido
SaquinavirAnxiety, Agitation, Euphoria
Depression, Hallucinations
Excessive dreaming
TipranavirDepression
Integrase Inhibitors
RaltegravirDepression, suicidal ideation, psychosis
Vivid dreams, nightmares, vertigo,
Lightheadedness/dizziness
ElvitegravirDepression, Insomnia, Suicidal ideation
DolutegravirInsomnia, Fatigue
Fusion Inhibitors
EnfuvirtideDepression, Insomnia

 

Psychotropics and HIV/AIDS

 

Benzodiazepines

  • 2/3 of medications prescribed for anxiety among HIV-infected individuals are BZDs
  • Individuals with HIV infection are particularly sensitive to the amnesic and paradoxical effects (disinhibition, confusion, agitation) of benzodiazepines

Benzodiazepines of choice for HIV patients

  • Clonazepam
  • Lorazepam
  • Oxazepam

 

Antidepressants

Antidepressants with the lowest CYP450 interactions are best first choice agents

  • Sertraline (weak 2D6 inhibitor) 
  • Citalopram
  • Escitalopram
  • Venlafaxine (weak 2D6 inhibitor)
  • Mirtazapine
  • Trazodone
  • Bupropion (potent 2D6 inhibitor but data supporting efficacy and tolerability)

 

Psychostimulants

Methylphenidate, Dextroamphetamine, and Amphetamine salts have all been used safely for

  • Apathy
  • Anhedonia
  • Low motivational drive (neglecting self care)
  • Fatigue
  • Pain/Neuropathy
  • Cognitive changes

 

Mood Stabilizers

  • Lithium is best choice
  • Valproate has been used safely and has minimal CYP450 interactions
  • Lamotrigine has been used safely for Bipolar Depression and neuropathic pain (metabolized by glucuronidation)
  • Gabapentin has been used safely for neuropathic pain and alcohol use disorders
  • Pregabalin did not separate from placebo in treatment of painful HIV neuropathy
  • Avoid Carbamazepine

 

Antipsychotics

  • First line for Psychosis: Atypical Antipsychotics (Start low, go slow. Avoid depot formulations)
  • HIV patients (especially late-stage) are generally more sensitive to Extrapyramidal Symptoms (EPS)
  • Avoid typicals (haloperidol, chlorpromazine) if possible
  • Avoid highly anticholinergic agents due to delirium risk and cognitive side effects
  • Avoid clozapine or pimozide with ritonavir (increases clozapine and pimozide levels dramatically)

 

Substance Use Disorders

 

Opioid Dependence

Buprenorphine better choice than methadone

Naltrexone has no CYP450 metabolism and is not expected to interact with antiretrovirals

Alcohol

Avoid Disulfiram

Use Naltrexone and/or Acamprosate

 

Naltrexone: Reduces cravings, rewarding effect, and amount of alcohol consumed at relapse

Give during heavy drinking to reduce heavy drinking days

Acamprosate: Reduces cravings and attenuates relapse

Give during abstinence or early relapse

 

Amphetamine Abuse

Bupropion with or without naltrexone

Topiramate with or without naltrexone

 

References

  1. Stern, T. A., Freudenreich, O., Fricchione, G., Rosenbaum, J. F., & Smith, F. A. (2018). Massachusetts General Hospital handbook of general hospital psychiatry. Edinburgh: Elsevier.
  2. S. J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill (pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
  3. Levenson, J. L. (2019). The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. Washington, D.C.: American Psychiatric Association Publishing.
  4. Gallego, L. Barreiro P, López-Ibor JJ. Psychopharmacological treatments in HIV patients under antiretroviral therapy. AIDS Rev. 2012 Apr-Jun;14(2):101-11.

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