36: HIV/AIDS

Infection with the human immunodeficiency virus (HIV) is associated with a range of psychosocial and neuropsychiatric complications. While HIV/AIDS has become a manageable chronic disease for many patients, living with HIV/AIDS continues to be a practical and psychospiritual challenge. Persons at highest risk for HIV/AIDS (we use the term HIV/acquired immunodeficiency syndrome [AIDS] to designate the entire spectrum of clinical manifestations of HIV disease, from asymptomatic infection through advanced AIDS) are disproportionately likely to suffer behavioral and mood disorders and to be socially disenfranchised and economically disadvantaged. Once infected, they must contend with a still stigmatized, and if untreated, a progressive medical condition. In addition, many people with HIV have other significant comorbidities, such as chronic hepatitis, psychiatric problems, and/or substance use, which may make adhering to HIV treatment more difficult. Although patients with HIV/AIDS can present with life-threatening neuropsychiatric sequalae of HIV (central nervous system [CNS], opportunistic infections, HIV dementia), most patients’ behavioral concerns are focused on maintaining medication adherence, maximizing quality of life, and managing lifestyle issues.

Human immunodeficiency virus is primarily transmitted through sexual exposure or shared injection drug paraphernalia (sharing needles). Initially, the epidemic was concentrated among gay men in cities; now new cases of HIV infection are disproportionately seen in socioeconomically disadvantaged populations, especially women and men of color. Some patients do not fit “classic” risk factor profiles. For example, a monogamous woman may be infected through her husband who is bisexually active. Although past HIV prevention programs successfully reduced rates of new HIV infections in gay men, incidence of new HIV infection in multiple patient populations is significant. These patient groups include men who have sex with men but who do not self-identify as “gay,” speed users who share straws for intranasal use, teenagers, elders, and women. In the United States, about one-quarter of the over 1 million HIV-positive persons have never been tested and are not aware of their seropositive status. In spite of the great advances in treatment, HIV/AIDS remains underdiagnosed and undertreated in the United States and worldwide.

In 2006, the Centers for Disease Control (CDC) formally modified its HIV screening recommendations from that of focused testing in high-risk groups and in high-prevalence settings to universal screening. In this paradigm, all patients between the ages of 18–64 years are encouraged to be tested as part of routine preventative care, and detailed consent procedures have been modified to an opt in or out of HIV testing as part of routine care. Newer rapid testing procedures allow for patients to receive their results at the time of testing, improving the number of patients who receive their results and facilitating triage for medical follow-up. Evolving HIV treatment paradigms stress early and even universal treatment of HIV-infected patients. Theoretically, “test and treat” strategies will benefit patients by optimizing immune function, and benefit communities by reducing HIV transmission. At the same time, getting HIV-infected patients tested and engaged in long-term treatment is a persistent challenge. “Engagement in care” is emerging as a model in which patients feel connected with their care providers and their medical care institutions, and correlates not only with retention in treatment but also with treatment success.

Integrating HIV screening and HIV prevention counseling into routine health care activities can facilitate this discussion in primary care settings. For example, following discussion of other lifestyle/health-related issues like cigarette smoking and exercise, sexual practice and substance use questions have a practical context. As in all patient interviews, open-ended questions with the use of specific and understandable language are most likely to put the patient at ease and generate accurate information. For example: Are you sexually active with men, women, both, or neither? How about in the past? What, if any, street drugs do you currently use, for example, speed, pot, etc? How about in the past?

The purpose of these screening questions is not only to identify which patients to test but to identify high-risk behaviors that may be modified, for example, through condom use or needle exchange. Thus, HIV testing is paired with HIV prevention counseling, pairing screening with harm reduction education. Harm reduction programs like needle exchange reduce the spread of HIV infection. Substance use, including alcohol, is highly correlated with unsafe sex behaviors, and patients need to be educated about the risk of combining recreational substances and sexual activity. Preexposure prophylaxis is a harm reduction strategy in which persons at high risk for HIV acquisition receive antivirals to prevent HIV infection. While studies document the biological effectiveness of this strategy, many operational challenges limit its widespread implementation.

Because HIV/AIDS is a significant underrecognized and undertreated public health problem in the United States, generalist practitioners in both outpatient and inpatient settings should be competent in screening and prevention. In addition, in an era in which HIV treatment has become simplified, more durable and better tolerated, another important role for the primary care provider is to help evaluate and address barriers to patient’s adherence to treatment. Mental health conditions from preexisting psychiatric disorders like bipolar disorder or from incident conditions like adjustment disorders are common in HIV-infected patients and require active diagnosis and treatment. In addition, cohort studies document a bidirectional relationship between HIV infection and mental health disorders: patients with psychiatric disorders are more likely to engage in high-risk behavior, whereas HIV acquisition can exacerbate mental health disorders.

Overview

Although the course of HIV/AIDS is different for every patient, some common clinical and life events are associated with psychological distress, ranging from mild anxiety and discouragement to feelings of despair and suicide. Although untreated HIV infection is generally fatal, it is now rare for treated HIV patients to die from their infection. However, many “successfully” treated patients may have disabling neurocognitive disorders (mild dementia, neuropathy) profound fatigue, chronic pain, and other disorders. Although the mechanism of some of these symptoms is unclear, it is evident that they are increasingly common. Whether these disorders are due to long-term HIV infection itself, HIV-induced autoimmune sequelae or HIV treatments remains unresolved. However, some HIV-infected patients are asymptomatic and able to lead normal lives: working full time, completing school, and having children.

Women and men with HIV benefit from empathic relationships with their medical providers and from connections with other HIV-positive people. For example, in adherence studies of adult women with HIV, a robust predictor of medication compliance was the patient’s perception of her relationship with the clinician. In addition, women who meet other women with HIV (through retreats, support groups, newsletters) are more likely to be medication adherent and to keep medical appointments.

In many urban areas, support groups exist for HIV patients from diverse risk groups (e.g., patients in recovery, gay men with HIV, and so on). In more rural and underserved areas, public health departments may offer case management services for people with HIV. In some cases, these case managers may be the only local source of information, clinician referral, and psychosocial support for patients.

For most patients, being told that they are infected with HIV is traumatic. Practitioners should anticipate this distress and counsel patients with up-to-date information, and arrange referrals to appropriate HIV care sources, including medical providers and support groups. Web sites can be excellent resources and are best complemented by local support services. Patients who test HIV positive may experience and express a variety of emotional responses. In general, practitioners should allow the patient to express his or her feelings, and should actively listen to the expressed emotions in a nonjudgmental manner. Effective use of empathic statements such as: “I can understand how difficult this must be for you” and “We can work on this together” can help the patient to feel a little less overwhelmed and helpless.

Clinicians should be alert to the potentially wide range of emotional responses expressed by patients and then check their understanding with a reflective statement such as “You seem quite saddened by this news.” Often, the emotion that unexpectedly wells up in the physician (e.g., sadness, anger, panic) may be indicative of what the patient is feeling. Physicians can use their own emotions as diagnostic information to gain insight into the patient’s feelings (see Chapter 2, “Empathy” and Chapter 3, “Giving Bad News”).

Paradoxically, although many persons seek testing to relieve the uncertainty of not knowing their status, testing positive for HIV can create additional uncertainty. Suddenly, they are confronted with not knowing how long they will remain well, who will care for them if they become ill or debilitated, how they will support themselves, and many other unknowns. The physician can help the patient cope with this sudden uncertainty by providing both information and emotional support. It may be helpful to say: “Many people who test positive are concerned because they do not know what to expect—is this true for you?” Some patients are comforted by the physician’s acknowledgment that they are the same person they were before the test, but now they possess new information about their health that can be addressed. For example, the clinician can say: “You are the same person today as you were yesterday, only now you know that you are HIV-positive. It is important that you have this information so that we can now work together to keep you healthy.” Patients should be given up-to-date information about treatment, prognosis, and other medical data, especially if they request it. It has been shown that distress can be decreased if patients are informed about their disease and the treatment options.

Other emotions that the seropositive patient may express include anger, fear, denial, and depression. Patients may feel angry for many reasons: about having an incurable illness, about perceived loss of control, about current or future discrimination. Some patients are angry at themselves for having become infected or at the partner who may have transmitted the virus to them. Allow patients to express their anger and frustration; often the anger dissipates with empathic listening.

Fear is often a less evident emotion and may need to be elicited with questions such as: “What are your major fears about HIV?” and “From your experience with other people with HIV, what kinds of things are most frightening for you?” These fears should be acknowledged as legitimate, and when possible, the physician can help the patient to deal concretely with those problems that can be anticipated and ameliorated. It may be helpful to have the patient make two lists dividing the current or anticipated problems into those that are to some extent controllable and those that are basically uncontrollable. The controllable problems can be addressed through specific problem-solving strategies, and the clinician should focus on emotion-handling skills for the uncontrollable problems and emotions that may arise (see Chapters 1 and 2).

Denial is a common response to the news of a positive HIV test. For some patients this initially may be a healthy way of not allowing themselves to feel overwhelmed. In fact, some people may need several months to a year to come to terms with the diagnosis. If, however, denial leads patients to harm themselves (e.g., by refusing potentially life-enhancing or life-extending treatment) or to harm others by exposing them to HIV, the physician should challenge the denial. This can be done gently, for example, by saying: “I can understand why you would wish that you were not HIV infected, but you are, and we need to deal with it.” Such statements may need to be repeated at subsequent visits until the patient is ready to accept the fact and consequences of their seropositive status.

Depression and anxiety are also common responses in persons who test positive for HIV. The clinician should assess the severity and duration of these symptoms to determine the appropriate treatment. Some studies have found that the risk of suicide is increased in the 3–6 months following a serologic diagnosis, so all patients should be screened for reactive depression and suicidal ideation. It is best to use direct, open-ended questions such as: “How are you handling your HIV diagnosis?” and “What fears or concerns do you have?”

In the weeks and months following a positive test, the clinician can assist patients in coping more effectively by assessing their social support system. This can be done by asking: “Who are you talking to about your concerns and issues?” If patients are isolated, provide them with phone numbers of local AIDS service organizations. Family members can also provide valuable support, but often HIV-infected people avoid seeking their help, or the family has previously rejected them because of their lifestyle. Clinicians can help patients by offering to have family or significant others attend medical appointments, and by integrating supportive others into the treatment team.

Managing Substance Use

Active substance use is a risk factor for HIV acquisition, for medical nonadherence, and for reexposure to HIV through unsafe sex and needle sharing. Many cases of new HIV infection are correlated with unsafe sex during alcohol or drug binges. Patients in drug and alcohol recovery have been shown to be able to achieve good adherence. All patients with current or past drug or alcohol problems should be screened for comorbid psychiatric disorders.

Methadone has significant interactions with nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). These interactions are not always predictable (e.g., one agent, nevirapine, can both raise and lower methadone levels). When antiviral drugs are changed, patients should be monitored for both methadone intoxication and withdrawal, and their methadone treatment center informed of the need to adjust the methadone dosage.

Many street drugs, for example, heroin and ecstasy, are metabolized by cytochrome P450 3A4 and 2D6 enzymes, enzymes that may be downregulated by a PI booster, ritonavir and cobicistat, an integrase booster. Inadvertent drug overdoses have occurred due to these interactions. Patients who continue to use street drugs and who are on antiretroviral therapy should be counseled in a harm reduction model about these potentially fatal interactions.

Involving patients in the timing and choice of antiviral medications may reduce their anxiety and improve long-term adherence. When patients know what side effects are possible and what the demands may be of different treatment regimens, they can assist the clinician in selecting the most workable antiviral combination. Adherence to a medication regimen is often a challenge for patients with chronic illness (see Chapter 20) and adherence to HIV medications is especially crucial for HIV-positive patients. Newer HIV treatment paradigms may be more or less “forgiving” of patient nonadherence, so skilled clinicians take these differences into account when selecting and reformulating an appropriate treatment regimen.

Ironically, although HAART adherence is critical to success, it is difficult to predict or measure. Multiple studies have revealed that even skilled HIV/AIDS practitioners are often inaccurate at assessing or predicting any individual patient’s medication compliance. Across studies, active substance use, untreated psychiatric and behavioral disorders, isolation, transportation problems, health system barriers (to visits or to pick up medications), and changes in routine are all risk factors for nonadherence. On the positive side, patients who experience their clinicians as knowledgeable, trustworthy, and approachable are more likely to comply with their medications, reinforcing the importance of the clinician–patient relationship. In institutions where medical turnover is high (e.g., residency programs, fellowships) engagement in care can be enhanced through continuity with another provider such as a case manager or social worker.

Clinicians should assess and address adherence initially and on an ongoing basis. Open-ended and supportive questions are useful: “How are you doing with remembering your meds?” “How many doses did you miss yesterday? Last week?” “Are you having any side effects that cause you to skip doses?” This assessment provides important clinical information and reinforces the critical importance of medication adherence for the patient.

For most patients, linking doses to routine activities (walking the dog, brushing teeth, waking the children) is helpful. Medisets, beepers, and periodic adherence checks by case managers may also be helpful. Clinicians can regularly reassess each patient’s regimen, considering off-label but studied dosing schedules that may be more user-friendly than on-label dosing. During periods when the patient is at high risk of nonadherance, temporarily suspending antivirals (a structured treatment interruption) may be preferable to poor adherence.

Hepatitis B & C Coinfection

All patients with HIV should be screened for chronic hepatitis B and C. For some patients learning they have chronic viral hepatitis, in addition to HIV, can be overwhelming. In addition, evaluation for treatment of hepatitis B and C may involve liver biopsy, and currently available treatments for hepatitis C (interferon, ribavirin) can cause severe flu-like symptoms and exacerbate major depression.

The clinician should assess each patient’s ability to cope with another diagnosis and plan diagnostic studies accordingly. Patients on an interferon-containing regimen should be closely monitored for depression. Although interferon treatment can exacerbate mental health conditions, many patients can tolerate these exacerbations and a mental health diagnosis alone should not preclude a patient from treatment. A recent study of patients with hepatitis C showed that those with mental health diagnoses had comparable adherence and virologic outcomes compared with patients without psychiatric diagnoses. In fact, with the advent of interferon-sparing hepatitis C (HCV) treatment regimens, most HIV/HCV co-infected patients will be candidates for HCV treatment.

Women

Isolation and stigma are especially common in women with HIV. Women may be especially fearful about disclosing their HIV status for fear of domestic abuse, loss of child custody, or loss of employment. Referral to local and national organizations is often helpful. Pregnant women with HIV benefit from multidisciplinary care teams that can both optimize their HIV care and provide appropriate perinatal care to mother and baby. They should be advised about the risks and appropriate management of perinatal transmission of HIV.

Chronic Pain

Chronic pain is a common complication of HIV disease. Specific causes of chronic pain include postherpetic neuralgia, peripheral neuropathy, avascular necrosis (AVN), and HIV myelopathy (spinal cord dysfunction). In 10% of HIV patients with chronic pain, a specific etiology is not found. Untreated pain can contribute to insomnia, depression, substance use, and medication nonadherence. Patients at highest risk of undertreatment are women, minority patients, and patients with prior or active substance use. Depression is a risk factor for chronic pain and should be screened for in all patients with pain disorders.

General pain management principles (see Chapter 35) can be applied in treating HIV-associated pain. Treatments for chronic pain include agents that elevate neurotransmitters both in the spine and brain; these include older treatments like low-dose tricyclic antidepressants (TCAs), and newer agents like serotonin norephinephrine reuptake inhibitors (SNRIs). Many analgesic and adjunctive medications (e.g., TCAs, carbamazepine, methadone) are metabolized through cytochrome P450 and may interact with NNRTIs and PIs. Gabapentin (Neurontin), Lamictal (lamotrigine), Lyrica (pregabalin), nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and aspirin have no significant interactions, but their use may be complicated by rash, sedation, renal dysfunction, and other side effects. In patients requiring narcotic therapy, longer-acting agents supplemented by fast-acting narcotics as needed for breakthrough are generally most effective.

Fatigue

Many patients with HIV, even those successfully treated with antivirals, suffer from disabling fatigue. Typically, patients wake with a good deal of energy only to develop severe fatigue with minor activities. Many patients will need to nap and sleep longer than was usual for them. Researchers have speculated that this fatigue may be due to cytokine effects in the brain, neuroendocrine dysregulation, and/or autonomic/circadian rhythm dysregulation.

Before ascribing fatigue to idiopathic HIV-associated fatigue, an extensive differential diagnosis should be considered including depression, anemia, testosterone, deficiency, sleep apnea, chronic hepatitis, hypothyroidism, chronic pain, and medication side effects. Idiopathic HIV-related fatigue may respond to bupropion (Wellbutrin), modafanil (Provigil, Nuvigil), or stimulants. Patients who are otherwise well and wish to resume a full life need validation that their fatigue is real and need to be informed that even with aggressive treatment their stamina may remain limited.

Management of Neuropsychiatric Complications of HIV/AIDS

Clinicians caring for HIV-infected patients must be able to identify specific syndromes (e.g., depression, psychosis), formulate preliminary differential diagnoses, and make appropriate psychotherapy and psychopharmacological referrals. HIV-related neuropsychiatric syndromes are evaluated and treated with the following guidelines:

1. HIV-associated opportunistic infections, which may present as behavioral disorders, are very uncommon in patients with more than200 CD4 cells or in patients with less than 200 CD4 cells and low or undetectable viral loads.

2. Side effects of prescription or over-the-counter medication commonly cause neuropsychiatric symptoms.

3. Drug interactions (both with prescription and recreational drugs) are of special concern in patients receiving potent suppressors of cytochrome P450 3A4 and 2D6, particularly ritonavir.

4. Recreational drug use and withdrawal can cause symptoms directly or exacerbate preexisting disorders (e.g., bipolar affective disorder).

5. With a few exceptions, HIV-associated neuropsychiatric symptoms are guided by the same treatment principles as for the general population; most psychiatric medications are used at the same dosages and for the same indications.

Some of the medications used to treat HIV/AIDS and its complications have common neuropsychiatric side effects. Side effects may be related to cumulative dose or to peak levels or may be unpredictable and idiosyncratic. Furthermore, in patients with advanced HIV disease, the homeostatic mechanisms responsible for maintaining therapeutic drug levels may be disrupted by end-organ involvement, such as decreased renal excretion, hepatic metabolism, or cardiac output; diminished body fat; immunologic dysregulation; and a predisposition toward dehydration. These patients with HIV are, therefore, also more susceptible to side effects from more commonly used medications. The rule of thumb for prescribing to persons with advanced HIV is “say no, start low, and go slow,” that is, avoid unnecessary medications, use reduced dosages of those that are necessary, and increase doses slowly and cautiously. Most patients, however, will require conventional doses of medications used to treat psychiatric disorders, so the edict “go slow” includes reaching therapeutic doses eventually.

Drug effects and toxicities must always be considered in the initial differential diagnosis of any neuropsychiatric abnormality. A few general principles should be kept in mind. First, use agents with favorable side effect profiles. Second, use caution in the coadministration of medications with similar side effect profiles or those that significantly affect one another’s pharmacodynamics. An example of the first situation is the simultaneous use of any combination of antidepressants, antihistamines, neuroleptics, or antimotility agents, all of which have substantial anticholinergic effects. The second concern arises in the use of agents, such as rifampin or rifabutin, which induces the hepatic cytochrome P450 enzyme system and thereby accelerates metabolism of many other drugs or conversely, agents such as ritonavir or delavirdine which inhibit the P450 enzyme.

A third concern is that adherence to complex medication regimens is often unreliable. Incorrect dosing may result in undertreatment for some conditions, but confusion may also result in inadvertent overdosing. Always simplify the regimen and use the lowest dose of the fewest drugs likely to be effective. The assistance of a pharmacist is invaluable in addressing these concerns. If possible, the regimens of patients with advanced HIV/AIDS or on multiple medications should be periodically reviewed by a pharmacist.

Persons with HIV/AIDS on average have higher levels of substance use, in part because of the association between preexisting drug use and the risk of acquiring HIV/AIDS, and perhaps because of self-medication for depression or anxiety. Stimulant drugs such as cocaine or amphetamines can cause agitation, psychosis, or delirium, as can withdrawal from sedating drugs such as benzodiazepines and alcohol. Sedatives and narcotics can not only cause somnolence, confusion, and psychomotor slowing but can also cause paradoxical reactions, including agitation, paranoia, and rage. This may be especially true of the short-acting benzodiazepines.

With regards to specific antiviral agents, two specific points need emphasizing. First, cobicistat or ritonavir-containing regimens, through inhibition of cytochrome P450 enzymes, may dramatically raise the level of many prescribed and recreational drugs. These substrates include many anticonvulsants (carbamazepine, valproic acid, phenytoin), narcotics (meperidine, methadone), recreational drugs (3,4-methylenedioxymethamphetamine [MDMA] or Ecstasy), and other agents (warfarin, digoxin, estrogen). Patients receiving these antivirals should be monitored for potential interactions (see Table 36-1).

Second, 2 weeks after starting efavirenz, patients may experience disrupted sleep, depression, agitation, and exacerbation of previously stable psychiatric disease. Whereas case and cohort studies report delayed or persisting neuropsychiatric symptoms due to efavirenz, a prospective double-blinded study failed to show any lingering or delayed CNS side effects attributable to the medication. Conversely, a recent cohort study showed an increased risk of suicidal ideation in patients taking efavirenz long term. Patients with stable psychiatric disorders may be prescribed efavirenz, but should be monitored for drug-associated agitation or depression. All patients who are starting efavirenz should be provided with sleeping medication for the first 2 weeks, either a standard benzodiazepine, or if substance misuse is a concern, a low-dose atypical antipsychotic.

Depression

Major depression is the most common psychiatric disorder in persons with HIV/AIDS. The lifetime incidence is unknown but rises dramatically as the disease progresses. As with non-HIV-infected depressed patients, the cardinal symptoms include depressed mood, anhedonia, feelings of worthlessness and hopelessness, disturbances in sleep and appetite, weight loss or gain, fatigue, psychomotor slowing, agitation, and preoccupation with morbid thoughts (see Chapter 25). A family history of an affective disorder or alcoholism may be present. Depression may be more difficult to diagnose in the presence of HIV/AIDS, however, for several reasons. First, its manifestations, and particularly the vegetative symptoms (fatigue, weakness, weight loss, and loss of libido) commonly overlap with the constitutional symptoms attributable to HIV infection or its complications. Second, organic impairment due to the HIV-associated dementia complex may have affective manifestations. Third, HIV-associated hypogonadism (low testosterone) may cause fatigue, impaired libido, and other depressive symptoms. For some patients, testosterone supplementation has been shown to reverse depressive symptoms. Finally, some medications and the use of or withdrawal from other psychoactive substances, can have mood-altering effects as described previously. Nevertheless, depressive disorders including major depression and dysthymia are diagnosed by the same criteria for HIV-infected as for non-HIV-infected persons and should never be treated as a normal finding. Indeed, recent surveys have documented that untreated depression is a major correlate of poor quality of life in people with HIV disease, and is an important risk factor for noncompliance with treatment.

Certain clues may help to distinguish depressive from constitutional symptomatology. For example, progressive fatigue that worsens with exertion and over the course of the day is characteristic of somatic disease (e.g., anemia), whereas an inability to get going in the morning, which improves with activity, may suggest depression. Similarly, nondepressed patients may report that nausea or dysgeusia (an abnormal sense of taste) interferes with their appetite, whereas depressed patients often report simply no interest in eating. Nondepressed patients often report their symptoms and limitations with frustration and concern, whereas apathy and resignation are more characteristic of major depression. Anhedonia and a sense of worthlessness are rarely symptoms of a somatic condition, and should therefore be directly investigated as specific indicators of depression. Depressed patients may appear more anxious or preoccupied than sad. Patients with depression and anxiety may self-medicate with recreational drugs or alcohol; patients with substance use should be screened carefully for depression and anxiety disorders.

The treatment of depression in HIV/AIDS does not differ from the non-HIV-infected population. Regular, empathic listening and short-term psychotherapeutic techniques may be effective. Explicit recognition and validation of the patient’s losses and fears help to establish a trusting therapeutic relationship and may permit developing joint strategies to cope with them. Emphasizing that depression is a common ailment in the setting of HIV/AIDS and is amenable to treatment is important. As with other patients, choosing among the many available agents should be largely a matter of selecting the most desirable or tolerable side effect profile.

The clinician must be alert to how the activity and toxicity profile of particular agents may help in simultaneously addressing other concerns of the patient. For example, appetite and sleep-stimulating medications such as mirtazapine may be effective in patients who suffer from insomnia. A TCA such as nortriptyline or an SNRI may be an ideal choice in a patient with neuropathic pain, who may also benefit from the drug’s pain-modulating effects. The risk of cardiac arrhythmias associated with tricyclic drugs may be increased in persons taking ritonavir. Bupropion is especially useful in patients with fatigue, and along with mirtazapine is unlikely to cause sexual dysfunction. Selective serotonin reuptake inhibitors (SSRIs) are especially useful in patients with anxious depression or comorbid anxiety disorders.

Stimulants may be used with other antidepressants in patients with severe refractory fatigue, and can also be used to palliate narcotic-associated fatigue and sedation. Because of their abuse potential, these agents must be used selectively, and their efficacy varies considerably from patient-to-patient.

Isolation from family, religious or spiritual community, or friends can result in demoralization. Because of the stigma of HIV within certain communities, HIV-infected patients may feel cut off from the usual sources of fellowship and support. Support groups, pets, engaged case management, and counseling can help prevent isolation.

Anxiety

As with some depressive symptoms, anxiety may be a normal response to many of the stressors associated with living with HIV. Symptoms of anxiety may include poor concentration, restlessness, preoccupation or intrusive thoughts, insomnia (particularly trouble falling asleep), and fatigue. Persons with poor coping skills may be particularly prone to periods of uncontrollable anxiety. Withdrawal from nicotine, alcohol, or illicit drugs, or overuse of caffeine may cause symptoms of anxiety.

Treatment is indicated if anxiety impairs social or occupational functioning, or is persistently uncomfortable. Pharmacotherapy generally involves the use of SSRIs and other serotonergic antidepressants, or benzodiazepines. For episodic and unpredictable bouts of anxiety, short-to medium-acting benzodiazepines, such as lorazepam (Ativan) or alprazolam (Xanax) are generally more effective, due to their more rapid onset of action. The physician should carefully monitor the frequency of refilling of anxiolytic prescriptions; a pattern of escalating use may suggest that a longer-acting agent or antidepressant therapy is preferable. For chronic disabling anxiety, longer-acting benzodiazepines such as clonazepam (Klonopin), which maintain more stable blood levels, may be more effective and better tolerated. Selective serotonin reuptake inhibitors are useful maintenance agents in the treatment of anxiety syndromes like panic disorder, obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD).

Patients with anxiety symptoms should be screened for PTSD. A recent study found that PTSD was the most robust predictor of medication and appointment non-adherence. Posttraumatic stress disorder symptoms include easy startling, flashbacks or nightmares, and dissociative symptoms. For some patients, the trauma of living with HIV rekindles memories of prior traumas (abuse, rape, accidents). Studies of incarcerated women with HIV have demonstrated a high rate of PTSD. Posttraumatic stress disorder is best treated with focused counseling, although SSRIs have been shown to help alleviate some of its symptoms.

Human immunodeficiency virus-associated dementia is a subcortical dementia initially characterized by cognitive and behavioral dysfunction, and in its most advanced stages by motor dysfunction. Advanced HIV dementia is rarely seen in patients with more than 200 CD4 cells or who are on effective antiviral therapy. Although antivirals differ in their penetration of cerebrospinal fluid (CSF), all combinations of antivirals that suppress serum viral load are likely to prevent HIV dementia. Rarely, genotypic analysis of CSF and blood reveals the presence of different HIV strains. In these cases, some experts recommend that antiviral medication may need to be adjusted to treat the CSF strains.

All patients with HIV dementia should be evaluated for comorbid depression, as depressive symptoms can easily be misattributed to dementia. A trial of antidepressants may result in gratifying functional improvement in these patients. As in all patients with organic brain disease, sedating agents like antihistamines and benzodiazepines should be used with great caution and in general avoided.

HIV-Associated Minor Cognitive Disorders

Although HIV dementia is rare in HIV patients undergoing treatment and in patients with more than 200 CD4 cells, minor cognitive problems can persist and even progress in patients with good surrogate markers (e.g., adequate CD4 cells and/or suppressed viral load). HIV-associated minor cognitive disorders are characterized by word-finding problems, difficulty sequencing complex tasks, and immediate memory dysfunction. Patients may note pauses in conversations while searching for words, difficulty performing clerical tasks, and difficulty multitasking.

Minor cognitive disorders may persist or progress in patients who are otherwise responding well to antiviral therapy. Although minor cognitive disorders tend not to progress, they are often disabling, despite patients appearing “normal.” These cognitive symptoms need to be carefully recorded in patients’ charts should disability status need to be assessed. Formal neuropsychiatric testing can document subtle cognitive dysfunction. Neuroimaging studies performed in research settings have correlated loss of both frontal lobe volume and frontal metabolic activity in patients with these symptoms. Standard mini-mental status tests are not appropriate diagnostic tools to diagnose minor cognitive disorder; the cognitive domains addressed in this tool are different from the executive task domains impaired in minor HIV cognitive disorder.

Mania

Mania can be a terrifying and dangerous complication of HIV/AIDS. As in non-HIV-infected persons, mania is characterized by hyperactivity and psychomotor restlessness, euphoric or irritable mood, insomnia and perceived decreased need for sleep, pressured or rapid speech, grandiosity or paranoia, racing thoughts, distractibility, hypersexuality, and reckless or disinhibited hedonistic behavior. Mania in HIV/AIDS can be due to a preexisting bipolar diathesis precipitated by substance use, stress, or intercurrent illness. Less frequently, mania may be an initial manifestation of HIV-associated organic brain disease like opportunistic infections or dementia. Medications reported to cause mania include high-dose corticosteroids, antidepressants, zidovudine, efavirenz, and stimulant drugs such as cocaine and amphetamine derivatives.

Treatment involves first discontinuing any potential pharmacological precipitant and ensuring a safe social environment. No specific antimania drug is best for HIV-associated mania—pragmatically, agents should be selected with the goal of calming the patient without undue sedation. Lithium, a mainstay of treatment for bipolar affective disorder in non-HIV-infected patients, may be more risky for patients with advanced AIDS in whom levels appear to fluctuate unpredictably. Dehydration, due to diarrhea, fever, or poor intake can quickly result in toxic lithium levels, further complicating management. However, lithium can be used safely in medically healthy HIV patients.

Psychosis

As with mania, psychotic symptoms are generally due to underlying psychiatric disease (schizophrenia) or drug (prescription, recreational) side effects. Psychotic symptoms include hallucinations, typically auditory rather than visual; delusions, which tend to be paranoid in content; looseness of association; and flight of ideas. Personal care and hygiene may be neglected, and medication adherence is poor. Use of or withdrawal from many illicit drugs, including amphetamines, phencyclidine, cocaine, alcohol, marijuana, and opiates, may cause a transient psychosis, and psychosis caused by methamphetamine in particular may last for days or weeks. Psychosis may complicate administration of the anticytomegalovirus drugs ganciclovir and foscarnet, anabolic or corticosteroids, zidovudine, efavirenz, opiates, other psychoactive pharmaceuticals including sedatives and antidepressants, and, very rarely, many ordinary antimicrobial agents. Psychosis is a rare manifestation of underlying secondary CNS infection or neoplasm.

Treatment of HIV/AIDS-associated psychosis involves identification and removal of precipitating drugs and treatment as appropriate. Psychiatric consultation is essential to confirm the diagnosis, identify possible secondary causes, and optimize management. Atypical antipsychotic agents are effective in acute and maintenance treatment of psychosis. These atypical agents are less likely to cause tardive dyskinesia and are less sedating than older agents.

Many patients with schizophrenia and HIV are “triply diagnosed,” that is, they also use recreational substances. These patients often benefit from day treatment programs where medical treatment is integrated with their mental health care, and where medication adherence can be facilitated through directly observed therapy.

Similar to all chronic medical disorders, HIV disease can be complicated by a myriad of psychiatric and spiritual challenges. Some patients acquire HIV as a consequence of their psychiatric disorders; others face psychospiritual challenges as they live with HIV. Although all patients benefit from accurate psychiatric assessment, patients also benefit from an ongoing relationship with a clinician they perceive as knowledgeable, caring, and trustworthy. In the authors’ experience, no other area of medicine requires such a skillful integration of the science and the art of medicine, nor offers such rewards for doing so.