Human Immunodeficiency Virus (HIV)
Joseph Gary, M.D., Matthew E. Peters, M.D., Glenn Triesman, M.D., Ph.D.
DEFINITION
DEFINITION
DEFINITION
- Human immunodeficiency virus (HIV) is a retrovirus (an RNA virus that uses reverse transcriptase to integrate its genetic material into host DNA) that infects CD4+ T cells and macrophages, causing progressive immune dysfunction. Without treatment, it can progress to acquired immunodeficiency syndrome (AIDS).
- The virus is transmitted by exposure to certain body fluids (blood, semen, rectal fluids, vaginal fluids, breast milk) from someone with HIV who has a detectable viral load. They must come into contact with mucous membranes, damaged tissue, open sores, or via injection with needle/syringe. Transmission is lower risk via oral sex, except if structural integrity of mucosal tissue is compromised (e.g. bleeding gums).
- After infection, viral replication begins, and there is a rapid rise in blood viral particles. Infectiousness is highest during this period. This is followed by immune response in the form of acute flu-like illness. Peak infectiousness increases again during advanced disease if left untreated.
- The development of multidrug antiretroviral therapies that target HIV-specific proteins has made it possible to completely suppress viral replication, although the virus is not eradicated, and there remains significant health consequences of HIV infection (chronic inflammation).
- Individuals who maintain an undetectable viral load cannot sexually transmit HIV.
- Strict adherence to ART is essential for viral suppression, and adherence challenges are often behavioral in nature.
- Psychiatric conditions have been shown to increase the risk of infection and decrease the likelihood of getting and adhering to treatment.
- Psychiatric disorders that may result from HIV infection are broad and include normal grief reactions, mood disorders, cognitive disturbances (including dementia and delirium), and behavioral disturbances (including substance-use disorders).
- Psychiatric disorders may be preexisting and have been a risk factor for getting infected or can be a consequence of damage from the virus (probably secondary to inflammation) or opportunistic infection.
- Although HIV infection can lead to a number of psychiatric sequelae, the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) only includes cognitive impairment due to HIV, which is classified in the neurocognitive disorders (NCDs) section[1].
EPIDEMIOLOGY
EPIDEMIOLOGY
EPIDEMIOLOGY
- In the U.S., The Centers for Disease Control and Prevention (CDC) estimates that 1.1 million persons aged 13 years and older are living with HIV infection[2][3]:
- A significant percentage are unaware of their infection (12-13%).
- Annual HIV diagnoses in the U.S. have been stable since 2016. In 2023, there were 39,201 new diagnoses.[3]
- Men who have sex with men (MSM) continue to be the most overrepresented group, along with Black/African American (39%), and Latino/Hispanic individuals.[3]
- Epidemiology of the psychiatric complications of HIV is presented below with each individual diagnosis.
DIAGNOSIS
DIAGNOSIS
DIAGNOSIS
Clinical Presentation
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
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
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
TREATMENT
TREATMENT
TREATMENT
General
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
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
Psychotherapy
WHEN TO REFER
WHEN TO REFER
WHEN TO REFER
- Given the polypharmacy associated with HIV treatment, and the fact that psychiatrists have the most expertise with psychopharmacy, it is recommended that HIV-infected patients with psychiatric comorbidity be followed by a psychiatrist.
- A psychiatrist can help determine the correct diagnosis and the needed length of treatment (psychotherapy, pharmacotherapy, etc.).
FOLLOW UP
FOLLOW UP
FOLLOW UP
- Patients diagnosed with HIV infection require routine monitoring for treatment response, medication side effects, and adherence.
- Given the very real concern for resistance associated with ART non-adherence, many clinics see patients monthly for medication refills and to ensure proper adherence.
- Psychiatric follow-up as indicated, but consider more regular follow-up if a psychiatrist has been asked to assist with interventions for ART adherence.
COMMENTS
COMMENTS
COMMENTS
- Psychiatric comorbidity with HIV infection is common, with some patients having premorbid conditions that predispose to HIV infection and some having psychiatric symptoms related to the HIV infection.
- By properly treating psychiatric symptoms, we hope to increase adherence to ART regimen, as well as patient satisfaction with life.
- For a review of the current medical treatment of HIV infection, we recommend The Johns Hopkins POC-IT HIV Guide.
- For a complete review of the psychiatric disturbances associated with HIV infection, we recommend The Psychiatry of AIDS: A Guide to Diagnosis and Treatment by Glenn J. Treisman, M.D., Ph.D., and Andrew F. Angelino, M.D.[10].
References
References
References
American Psychiatric Association. (2022). Diagnostic and statistical manual of mental disorders (5th ed., text rev.; DSM-5-TR).
CDC. Prevalence of Diagnosed and Undiagnosed HIV Infection — United States, 2008–2012. MMWR 2015; 64:657-662.
- Heaton RK, Clifford DB, Franklin DR, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75(23):2087-96. [PMID:21135382]
- Gibert CL. Treatment Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents: An Update. Fed Pract. 2016;33(Suppl 3):31S-36S. [PMID:30766213]
- Łupina K, Nowak K, Lorek D, et al. Pharmacological advances in HIV treatment: from ART to long-acting injectable therapies. Arch Virol. 2025;170(9):195. [PMID:40826301]
- Thompson A, Silverman B, Dzeng L, et al. Psychotropic medications and HIV. Clin Infect Dis. 2006;42(9):1305-10. [PMID:16586391]
Treisman GJ and Angelino AF. (2004). The Psychiatry of AIDS: A Guide to Diagnosis and Treatment. (1st ed.). Baltimore, MD: Johns Hopkins University Press.
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