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Evidence-Based Reviews


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

Vol. 3, No. 8 / August 2004

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)

  1. Acquired cognitive/motor/behavioral abnormalities, verified by reliable history and neuropsychological tests
  2. Mild impairment of work or activities of daily living
  3. Does not meet criteria for HIV dementia or HIV myelopathy
  4. 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

  1. Acquired abnormality in at least two of the following cognitive abilities (present for 1 month)
  2. At least one of the following:
  3. Absence of clouding of consciousness during a period long enough to establish the presence of criterion 1
  4. 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.

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