Psychiatric patients—especially those with substance abuse disorders—are at high risk for HIV infection, which puts psychiatrists on the AIDS pandemic’s front lines.

In the wake of last month’s International AIDS Conference in Thailand, this article supplements American Psychiatric Association guidelines for managing patients with HIV/AIDS.¹ Here is updated information on:

who is at greatest risk for HIV infection today
neuropsychiatric side effects of HIV medications
in-office assessment of HIV-associated cognitive changes
how to avoid psychotropic/antiretroviral interactions.

HIV and psychiatric patients

Psychiatric patients are among those at highest risk for HIV (Box).^2-4 Cournos and McKinnon⁵ found that HIV seroprevalence among persons with severe mental illness was 4% to 23%compared with 0.4% in the general population.⁶ They defined severe mental illness as schizophrenia, schizoaffective disorder, major depression, or bipolar disorder accompanied by significant functional impairment, disruption of normal life tasks, periods of hospitalization, and need for psychotropics.

Infection rates varied with HIV geographic concentration, presence of comorbid substance use disorders, age, and ethnicity, but not psychiatric diagnosis. Unsafe sex and drug use (including noninjection) were associated with infection, and women were as likely to be infected as men.

Side effects and interactions

‘Triple therapy.’ Combining three antiretroviral agents—highly-active antiretroviral therapy (HAART) or “triple therapy”—is standard treatment for HIV infection in the United States. Initially, HAART was recommended for all patients with early-stage HIV, even if asymptomatic. This changed as antiretrovirals’ side effects—such as peripheral neuropathy with didanosine— and drug resistance from suboptimal adherence became apparent. Viral resistance develops if patients are <95% adherent to antiretroviral regimens.⁷

Antiretroviral therapy is usually started when:

CD4 lymphocyte count is <200 cells/mm3 or abruptly decreasing
plasma viral load is >55,000 copies/mL or abruptly increasing
symptomatic AIDS emerges.

Psychiatric side effects. Psychiatric symptoms—such as depression, anxiety, confusion, psychosis, hallucinations, insomnia, and mania—are common side effects of antiretrovirals and other drugs used to treat HIV and its opportunistic infections and cancers (Table 1).⁸ Two antiretrovirals are of particular interest to psychiatrists:

Efavirenz is a non-nucleoside reverse transcriptase inhibitor that causes vivid dreams, especially when initiated.

Box

U.S. high-risk factors for HIV: Age under 25, male-to-male sex, drug use

AIDS death rates have declined in the United States since antiretroviral therapies were introduced in 1996, but the rate of new HIV infection has not changed.² An estimated 850,000 to 950,000 Americans have HIV, and 25% do not know it.³

Changing demographics. Some 40,000 new HIV infections occur in the United States each year (70% among men), and one-half of the newly-infected are under age 25. African Americans and Hispanics represent 51% of total AIDS cases in men and 77% in women. From 1998 to 2002—the most recent data available from the Centers for Disease Control and Prevention (CDC)—AIDS incidence steadily decreased among whites and Hispanics but increased among blacks, Asian/Pacific Islanders, and American Indian/Alaska Natives.

Transmission routes. Approximately 60% of men with HIV are infected through male-to-male sex, 25% through IV drug use, and 15% through heterosexual sex. Unprotected anal sex appears to be occurring more frequently in some urban centers, particularly among young men who have sex with men.⁴ Approximately 75% of women with HIV are infected through heterosexual sex and 25% through IV drug use.

Ritonavir is a protease inhibitor that may inhibit psychotropics metabolized by cytochrome P450 3A4 and 2D6 isoenzymes.

Other HIV medications increase or decrease psychotropic blood levels via inhibition or induction of CYP isoenzymes (Table 2).⁹ When a patient is taking ritonavir or another protease inhibitor, reduced starting dosages of selective serotonin reuptake inhibitors (SSRIs) may be appropriate. Benzodiazepine dosages may need to be increased because of ritonavir induction of the enzyme glucuronosyltransferase.

Table 1

Psychiatric side effects of common HIV medications

Drug	Side effects, by frequency
Acyclovir	Unknown: hallucination, confusion, thought insertion, insomnia
Amphotericin B	>5%: confusion, insomnia, somnolence; 1-5%: agitation, anxiety, depression, hallucination, nervousness, psychosis; Unkown: delirium
β-Lactam antibiotics	<1%: insomnia, somnolence, anxiety, nervousness, impaired concentration, confusion, nightmares, hallucination; Unkown: paranoia, mania
Trimethoprim/sulfamethoxazole	Unknown: hallucinations, depression, apathy, nervousness
Cycloserine Unknown:	psychosis, somnolence, depression, confusion, irritability, anxiety
Didanosine	Unknown: nervousness, anxiety, confusion, seizures, insomnia
Efavirenz	13-16%: depression; 8-11%: anxiety; 2-6%: nervousness; >5%: headache, seizures, confusion; <2%: suicidal ideation and behavior, aggression
Unknown:	agitation, lability, neurosis, psychosis, insomnia, impaired concentration, somnolence, euphoria, amnesia, hallucination
Foscarnet	>5%: depression, confusion, anxiety; 1-5%: insomnia, somnolence, amnesia, nervousness, agitation, aggression, hallucination
Interferon-a	6-19%: depression; 12-16%: irritability; 6-12%: insomnia; 3-8%: impaired concentration; >5%: anxiety: <5%: confusion, mania, aggression, delirium, lability, suicidal ideation, psychosis, personality disorder, alcohol intolerance
Isoniazid	Unknown: depression, agitation, hallucination, paranoia, anxiety, psychosis
Lamivudine	<11%: insomnia; <9%: mania, depressive disorders, dreams
Methotrexate	Unknown: cognitive and mood changes
Pentamidine	Unknown: confusion, lability, hallucination; Rare: anxiety, fatigue
Procarbazine	Unknown: hallucination, depression, nervousness, apprehension, mania, loss of appetite, insomnia, nightmares, confusion, malaise
Quinolones	<1%: somnolence, insomnia; Occasional: agitation, anxiety, depression, panic attacks, confusion, hallucination, aggression, psychosis, paranoia;
Rare:	suicidal ideation and suicide (no relationship with drug confirmed)
Stavudine	Unknown: confusion, depression, seizures, anxiety, mania, sleep problems
Sulfonamides	Unknown: psychosis, delirium, confusion, depression, hallucinations
Thiabendazole	Unknown: hallucination, fatigue, irritability, confusion, depression
Vinblastine	Unknown: depression
Vincristine	Unknown: hallucination
Zalcitabine	Unknown: acute psychosis, agitation, amnesia, anxiety, lability, euphoria, hallucination, insomnia, mania, paranoia, suicidal behavior, confusion, impaired concentration, somnolence, depression
Zidovudine	Unknown: Insomnia, vivid dreams, agitation, mania, hallucination, confusion

Table 2

Psychotropic/HIV drug interactions, by cytochrome P-450 isoenzyme

	CYP 3A4	CYP 2D6
Psychotropics primarily metabolized by isoenzyme	Benzodiazepines Buspirone Carbamazepine Citalopram Clomipramine Imipramine Trazodone	Fluoxetine Fluvoxamine Mirtazapine Antipsychotics (typical and atypical) Paroxetine Sertraline Tricyclics Venlafaxine
HIV drugs that inhibit isoenzyme	Protease inhibitors (esp. ritonavir and indinavir) Clarithromycin Erythromycin Itraconazole Ketoconazole Macrolide antibiotics	Protease inhibitors (esp. ritonavir and nelfinavir)
Possible clinical effect	Increased plasma levels and increased side effects; for benzodiazepines, sedation and decreased respiratory drive	Increased plasma levels and increased side effects; for tricyclics, increased risk for cardiac conduction delay
HIV drugs that induce isoenzyme	Nevirapine Efavirenz Glucocorticoids Rifampin Rifabutin	None
Possible clinical effect	Decreased psychotropic plasma levels, decreased effectiveness	None
Source: Adapted and reprinted with permission from reference 1, Table 16. Copyright 2000. American Psychiatric Association

The FDA approved enfuvirtide—the first of the new fusion inhibitor class of antiretroviral agents—in March 2003. Enfuvirtide prevents HIV from entering the target CD4 lymphocyte in patients who show continued viral replication despite ongoing antiretroviral therapy. This agent requires twice-daily subcutaneous injections. Because enfuvirtide can be viewed as a medication of last resort, nonresponse may be especially disheartening to an AIDS patient.

Substances of abuse also interact with HIV medications. A lethal overdose of the street drug MDMA (“Ecstasy”) has been reported in a patient treated with ritonavir.¹⁰ MDMA is metabolized primarily via CYP 2D6. Other substances of abuse metabolized by CYP 2D6 or 3A4—such as amphetamines, ketamine, heroin, cocaine, and gamma-hydroxybutyrate—may cause toxic reactions in patients being treated with protease inhibitors.

Because substance abuse is a common comorbidity of HIV infection, warn patients that using recreational drugs with antiretroviral medications can cause adverse reactions. Extensive drug interaction lists are available on patient education and physician Web sites (see Related Resources).

Table 3

Diagnostic criteria for HIV-associated minor cognitive motor disorder

Probable diagnosis (must meet all four criteria)

Acquired cognitive/motor/behavioral abnormalities, verified by reliable history and neuropsychological tests
Mild impairment of work or activities of daily living
Does not meet criteria for HIV dementia or HIV myelopathy
No other etiology present

A possible diagnosis of minor cognitive motor disorder can be given if criteria 1-3 are present and either:

an alternate etiology is present and the cause of criterion 1 is not certain
or the etiology of criterion 1 cannot be determined because of an incomplete evaluation

Source: Reprinted with permission from reference 14

Lipid and hyperglycemic side effects. Antivirals— especially protease inhibitors —appear to be associated with HIV lipodystrophy, which is associated with cosmetic and serum lipid changes as well as hyperglycemia.¹¹ Facial wasting, buffalo humps, and central intra-abdominal obesity may occur, and elevated serum cholesterol and triglycerides often require treatment with cholesterollowering “statin” drugs.

Though it is unclear whether HIV lipodystrophy increases cardiovascular disease risk, carefully consider the potential effects of psychotropics associated with weight gain, hyper-glycemia, and elevated lipids in patients receiving antiretroviral therapy.

Hepatitis. Patients at risk for HIV infection are also at risk for viral hepatitis. One-quarter of persons with HIV are coinfected with hepatitis C, primarily through IV drug use.¹² Alpha-interferon treatment of hepatitis B and C has been associated with depression. SSRI treatment—such as paroxetine, 20 mg/d—can ease depressive symptoms.¹³

HIV-associated cognitive changes

Minor cognitive-motor disorder(Table 3) and HIV-associated dementia (Table 4) ¹⁴ are typically seen in late-stage HIV infections and are diagnoses of exclusion. Physical or neurologic examination in a patient with HIV/AIDS and altered mental status may show:

focal deficits indicating a space-occupying lesion (eg, CNS lymphoma or toxoplasmosis)
sensory changes that may indicate peripheral neuropathy
ataxia or gait changes that may indicate myelopathy.

Useful neuropsychological tests include the HIV Dementia Rating Scale,¹⁵ Halstead finger-tapping test for motor speed,¹⁶ and the Trailmaking Test, which assesses psychomotor speed and sequencing ability.¹⁷

Antiretroviral therapy appears to reduce the risk of HIV-associated dementia. In a trial conducted at 42 AIDS Clinical Trials Group sites and 7 National Hemophilia Foundation sites, combination reverse transcriptase inhibitors helped preserve or improve neurologic function.¹⁸

Psychostimulants appear to improve HIV-induced brain impairment.¹⁹ Immune modulators—such as tumor necrosis factor-alpha blockers (eg, pentoxifylline)²⁰ and interleukin-1 receptor blockers²¹ —have also been studied for possible beneficial effects on HIV brain disease.

HIV prevention

Because unprotected sex and IV substance use are the primary HIV transmission routes in the United States, assessing psychiatric patients’ sexual and substance use behaviors may help you prevent HIV infection. The CDC offers guidelines for HIV testing, counseling, and referral (see Related Resources).

To identify persons at risk for HIV infection, the CDC recommends asking open-ended questions about risk behaviors, such as: “What are you doing now or what have you done in the past that you think may put you at risk for HIV infection?”²²

The shift of new HIV infection disproportionately into African-American and Hispanic populations suggests the need for more-intensive prevention and education in those communities. CDC guidelines emphasize the importance of using culturally sensitive language when asking about risk behavior. Some individuals may engage in same-sex behaviors but do not identify themselves as “homosexual” or “gay.” In some African-American communities, for example, being “on the down low” is used to describe men—oftentimes married—who have sex with men.

To incorporate HIV-prevention messages and brief behavioral interventions into clinical visits:

speak with patients about sexual and drug use behaviors in simple, everyday language
learn about interventions shown to be effective
become familiar with community resources that address HIV risk reduction.²³

Training. The CDC and Health Resources and Services Administration of the U.S. Department of Health and Human Services offer free training on risk screening and prevention, as well as opportunities for continuing medical education (see Related Resources).

Table 4

Diagnostic criteria for HIV-associated dementia

Acquired abnormality in at least two of the following cognitive abilities (present for 1 month) At least one of the following: Absence of clouding of consciousness during a period long enough to establish the presence of criterion 1 Exclusion of another etiology
Source: Reprinted with permission from reference 14

Advances in antibody testing

Psychiatrists play an important supportive role in encouraging HIV screening of at-risk patients of unknown serostatus and in counseling such patients before, during, and after test results are known.

Rapid lab tests. In 2002, the FDA approved a rapid, highly accurate HIV-1 screening test for serum specimens and in March 2004 approved the same test for screening oral fluid specimens. Test results with serum or an oral swab are available from a laboratory in approximately 20 minutes. In clinical studies submitted to the FDA, the OraQuick oral fluid test correctly identified 99.3% of persons infected with HIV-1 (sensitivity) and 99.9% of those not infected (specificity).

CDC guidelines for HIV counseling and testing have been revised to include rapid testing. Screening tests are most accurate at least 3 months after an HIV exposure—the time required for antibodies to develop. When counseling patients after a reactive test result, emphasize that the result is preliminary and further testing is needed to confirm the result. Counsel patients who have a negative result within 3 months of possible infection to be retested to guard against a possible false-negative result.

Home test kits. An FDA-approved consumer-controlled test kit—Home Access HIV-1 Test System²⁴ —is sold at drug stores without a prescription. The customer pricks a finger with a special device, places drops of blood on a specially treated card, and mails the card to a licensed laboratory. Anonymous identification numbers are used when phoning for the results.

Customers may speak to a counselor before taking the test, while awaiting results, and when results are given. All individuals with a reactive test result are referred for a more-specific test and receive information and resources on treatment and support services.

Counseling the HIV patient

The psychological impact of positive HIV antibody test results on psychiatric patients has not been studied. Persons without psychiatric disorders commonly experience anxiety and depression immediately after learning of a positive result. Unless the patient has HIV-related physical symptoms, these psychological sequelae often return to baseline—similar to when the blood sample was drawn—within 2 weeks.²⁵

Patients need to know that a positive HIV test result is no longer associated with death within 2 to 3 years. During a 2-year period, for example, disease progression from HIV infection to AIDS decreased 7-fold among patients who started antiretroviral therapy with a CD4+ T-cell count >350 cells/mm3, compared with others who were monitored without therapy.²⁶ This may be especially important to reinforce with newly-diagnosed patients unfamiliar with advances in HAART.

Medication adherence. To increase patients’ adherence to antiretroviral therapy:

express interest that they are taking their medications
use psychotherapy to help them solve problems that interfere with adherence.

Suicide risk. In the 1980s, significantly increased suicide rates were reported among HIV-infected persons. For example, the suicide rate in 1985 for New York City men ages 20 to 59 living with an AIDS diagnosis was 36 times higher than that of similar men without AIDS.²⁷ A later study of HIV infection in New York male suicide victims from 1991 to 1993 suggested that HIV serostatus was associated with a modest increase—at most—in suicide risk. That study considered the interplay of other suicide risk factors, such as substance abuse.²⁸

Related resources

Guidelines for HIV counseling, testing, and referral. Centers for Disease Control and Prevention. www.cdc.gov/mmwr/preview/mmwrhtml/rr5019a1.htm
Training in HIV prevention and counseling. National Network of STD/HIV Prevention Training Centers (http://depts.washington.edu/nnptc) and AIDS Education and Training Centers National Resource Center (http://www.aids-ed.org)
Rapid HIV testing. Centers for Disease Control and Prevention. http://www.cdc.gov/hiv/rapid_testing/
Cytochrome P450 drug interaction table. Indiana University School of Medicine. Division of Clinical Pharmacology. www.drug-interactions.com

Drug brand names

Buspirone • BuSpar
Carbamazepine • Carbatrol
Citalopram • Celexa
Clomipramine • Anafranil
Fluoxetine • Prozac
Fluvoxamine • Luvox
Imipramine • Tofranil
Mirtazapine • Remeron
Paroxetine • Paxil
Sertraline • Zoloft
Trazodone • Desyrel
Venlafaxine • Effexor

Disclosure

Dr. Liang reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products

Using psychotropics safely in patients with HIV/AIDS: Watch for drug-drug interactions with antiretrovirals