1. Pathophysiology and virology

Identified in 1984, HIV is a human retrovirus (Figure 1). A retrovirus contains RNA as its genetic material as well as the enzyme reverse transcriptase required to translate RNA into DNA within the human host cell. Once HIV RNA is transcribed into human DNA through the process of replication, it becomes a functional virus capable of producing profound immune deficiency, particularly cell-mediated immune dysfunction (Figure 2).

As with other retroviruses, HIV has a rapid rate of genetic mutation. HIV-1 is the form of the virus that causes disease in most of the world, including the United States, Europe, Asia, Latin America, and most of Africa. HIV-2, discovered in 1986, causes a relatively small proportion of cases clustered in West Africa. Unless specified, the term HIV used in this guideline will refer to HIV-1.

HIV selectively infects certain cells within the human body, with the primary sites being blood mononuclear cells, particularly T-helper (CD4) lymphocytes and lymphoid tissues. HIV is neuropathic, invading the CNS early during the initial period of infection.

Counter to earlier beliefs, HIV does not become "dormant" but rather engages in an extraordinary battle with the immune system that begins and continues after initial infection. Once a host is infected with HIV, the virus begins a process of rapid replication, with billions of viral particles made soon after infection (Figure 3). At the same time, the host immune system mounts a response. The capacity of HIV to infect host cells and replicate, destroying CD4 cells in the process, is counteracted by the capacity of the host immune system to produce and maintain immune surveillance over the replicating virus. Current knowledge suggests that there is a viral "set point" that varies among individuals and constitutes a balance between viral reproduction and the immune response. This viral set point has prognostic significance (1). The growth of knowledge about the virology and pathophysiology of HIV has had enormous implications for treatment interventions.

2. Epidemiology of HIV/AIDS

HIV infection is a global pandemic, with cases of AIDS reported in nearly every country in the world. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), as of December 1999, more than 33 million people in the world are estimated to be living with HIV/AIDS, of which 95% live in the developing world. Globally, more than 16 million people have died of AIDS since the epidemic began (data available at http://www.unaids.org).

The Centers for Disease Control and Prevention (CDC) monitors the incidence, prevalence, morbidity, and mortality from HIV/AIDS in the United States (http://www.cdc.gov/nchstp/hiv_aids/dhap.htm). Through December 1999, a cumulative total of more than 730,000 AIDS cases have been reported to the CDC; there have been 430,441 total deaths from AIDS in the United States (Table 1). Approximately 650,000–900,000 persons in the United States are currently infected with HIV, which is about 0.3% of the population or 1 in 300 Americans.

In recent years, there has been a remarkable change in the epidemiology of AIDS in the United States. The National Center for Health Statistics has reported that age-adjusted death rates from AIDS in the United States declined an unprecedented 47% from 1996 to 1997, and AIDS fell from 8th to 14th among leading causes of death in the United States over the same time (2). For those aged 25–44, AIDS dropped from the leading cause of death in 1995 to the third-leading in 1996 and the fifth-leading in 1997 (2). The drop in deaths and AIDS incidence has been attributed to the effectiveness of antiretroviral therapy, but the declines have been less apparent among women and minorities.

At the same time, a study by the CDC found that despite the decrease in AIDS deaths and incidence, the rate of new HIV infections has remained the same: about 40,000 new cases a year (3). Therefore, the overall prevalence of HIV infection in the United States has increased (4). Prevention of HIV infection remains a high priority.

Approximately 70% of new infections occur among men, of which 60% are men who have sex with men, 25% are injection drug users, and 15% are men exposed through heterosexual contact (3). Among women, 75% of new infections occur through heterosexual contact and 25% through injection drug use (5). African American and Hispanic communities are two distinct populations within which women, youth, and children are especially affected.

3. Transmission of HIV

HIV is transmitted through body fluids. It has been isolated from a variety of body fluids, including blood, semen, vaginal secretions, breast milk, urine, saliva, and tears. The risk of transmission through contact with a given fluid is related both to the amount of virus present in the fluid and to the type of exposure to it. HIV is found in such small concentrations in tears, saliva, and urine that transmission through casual contact with these fluids is theoretically possible but highly unlikely. On the other hand, behaviors that lead to certain types of exposure to blood, semen, vaginal secretions, and breast milk—all fluids with higher HIV concentrations—may lead to HIV transmission. HIV is spread primarily by unprotected sexual intercourse, irrespective of gender or sexual orientation, and sharing of unsterilized injection equipment for either medical or illicit purposes. It can be transmitted from an infected mother to an infant in utero during pregnancy, perinatally, or through breast-feeding.

a) Sexual

Sexual behaviors with exchange of body fluids can transmit HIV. While the rate of HIV transmission is somewhat higher for the recipient of semen than for the donating sexual partner, transmission has been documented in both directions. Penile-anal and penile-vaginal intercourse are considered the highest risk behaviors, with transmission more likely in the presence of other sexually transmitted diseases or genital lesions or during sexual activities that cause a rupture of tissue or bleeding (Table 2).

b) Injection drug use

Sharing the equipment used to prepare and inject drugs with an HIV-infected person is a very efficient means of transmitting HIV and essentially amounts to a direct inoculation of viral particles from one person to another. The risk of transmission is directly related to the concentration of virus present in the blood and the volume of blood exchanged. Injection drug use is the second most common risk factor for HIV infection, and injection drug users account for an increasing proportion of AIDS cases (24% in 1997). It has been estimated that there are more than 1.5 million injection drug users in the United States (7).

c) Blood transfusion

Blood transfusion with infected blood products remains a significant risk for acquiring HIV in some parts of the world. In the United States, donated blood has been screened for antibodies to HIV-1 since 1985 and for antibodies to HIV-2 since 1992. Therefore, the risk of transmission from a blood transfusion has become extraordinarily low—less than 0.001%. To further ensure that donated blood is not infected with HIV, since 1996 the American Red Cross has used the HIV antigen test. This test helps address the problem of false-negative HIV antibody tests in donors who may not have produced detectable antibodies after their initial infection. Before the use of lyophilized factor VIII, recurrent inoculation with pooled donated factor VIII was a major source of HIV transmission in hemophilia patients.

d) Perinatal

Infection from mother to infant can occur during gestation, delivery, or breast-feeding. Because breast milk contains significant numbers of lymphocytes that can lead to HIV transmission from mothers to newborns, it is recommended in the United States and other developed countries that HIV-infected mothers bottle-feed and not nurse their infants.

e) Cofactors for transmission

Cofactors can enhance but do not cause the transmission of HIV. Physical cofactors include the presence of sexually transmitted diseases (such as gonorrhea, syphilis, and chlamydia, which may cause genital lesions) or genital/mucous membrane bleeding during sexual activity. The use of mood or mind-altering substances may serve as a behavioral cofactor because they can lower sexual inhibitions, impair judgment, or increase impulsivity. Data are inconclusive regarding the effect of mind-altering substances on immunocompetence and HIV susceptibility or progression.

4. Pathogenesis of HIV

Three to 6 weeks after initial infection with HIV, there is a burst of viral replication, with wide dissemination of the virus throughout the body, particularly in lymphoid tissue and within the CNS. During this acute phase, approximately 50%–90% of people will experience a nonspecific "flu-like" syndrome of varying severity with fever, sore throat, rash, lymphadenopathy, and splenomegaly. Others do not have this seroconversion syndrome and may be unaware of their infection (8). As the host's immune system begins to recognize the pathogen and mounts a response to control the infection, plasma viral titers may drop 100-fold within 1 or 2 months of initial infection. When the host produces circulating antibodies against HIV, the host is said to "seroconvert," demonstrating a positive HIV antibody test. Although the immune system may appear to control the initial infection, chronic viral replication persists. There have been recent discoveries that "resting CD4 T cells" become infected rapidly after HIV transmission, and once HIV hides within resting T cells, antiretroviral therapy is unlikely to affect this sanctuary for HIV (9, 10).

The acute phase is followed by a clinically asymptomatic phase, during which the body has established a dynamic balance between the capacity of the virus to replicate and infect new CD4 cells and the capacity of the body to produce more CD4 cells. Even so, as many as 10 billion viral particles are produced daily, with a plasma virus half-life of about 6 hours. The asymptomatic phase may last for many years until symptoms arise that indicate that HIV infection is progressing. Progression to a symptomatic phase of illness may occur more rapidly in those with immune systems that are compromised before HIV infection and in infants with undeveloped immune systems. Other factors influencing disease progression include mutations of cell surface receptors and host factors such as HIV-specific cytotoxic lymphocyte response (Figure 3).

Viral load, a measurement of how many viral particles are present in a cubic millimeter of blood, is determined by several different assays that can detect as few as 20 viral particles per cubic millimeter of blood. Below that threshold, viral load is reported as "nondetectable." This does not mean that there is no HIV in the blood. Furthermore, this method does not measure the amount of HIV in lymphoid tissue, semen, or CNS. While some studies have shown a small correlation between serum viral load and lymphoid tissue and CSF viral load, in later stages of HIV infection, plasma and CSF viral load are largely uncorrelated (11, 12). Thus, the CNS can be seen as an independent "reservoir" of HIV replication. Current practice is to use serum viral load measurements, in combination with assays of immune cells such as CD4 counts and genotypic testing for viral resistance, to guide clinical decisions about the initiation of or changes in antiretroviral medication (13–15).

New knowledge about the life cycle of HIV and the discovery of several classes of medications that disrupt the virus at different points in the replication cycle (Figure 4) benefit many patients who receive multidrug regimens, known as potent, combination, or highly active antiretroviral treatment. However, these regimens—which involve at least three medications, with short- and potential long-term side effects, taken multiple times per day for the life of the infected person—require strict adherence. The behavioral and psychological burden of early intervention is thus a mitigating factor against such an early and aggressive treatment approach. The rapid pace of changes to potent, combination, or highly active antiretroviral treatment guidelines adds to uncertainty about such interventions. Medications that can be taken less frequently are being developed to make the regimens more manageable.

5. Assessment and staging of HIV disease

HIV infection usually leads to clinical diseases that affect almost every organ system and present with a wide range of symptoms and syndromes. Accurate assessment and diagnosis of systemic as well as CNS impairment requires close medical and psychiatric management, with increasing vigilance as immune competence declines and the possibility of life-threatening disorders increases.

The CDC Revised Classification system for HIV infection and AIDS used CD4 counts and staging of illness (Table 3) to establish clinical categories for HIV disease. Generally, AIDS is defined by certain conditions marking advanced immunosuppression, such as a diagnosis of opportunistic infections (e.g., Pneumocystis carinii pneumonia) or other conditions (e.g., dementia or wasting). AIDS-defining criteria are listed in Table 4.

6. Treatment for HIV infection

Most of the world's HIV-infected population has little if any access to antimicrobial therapies for consequences of immune deficiency, let alone combination antiretroviral treatment. In the United States, revised standards of care for the treatment of HIV infection have improved treatment effectiveness, increased survival for patients, and potentially lessened development of viral resistance. Treatment is accomplished through numerous combinations of antiretroviral agents from four classes: nucleoside analogue reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, and the newest class, nucleotide analogues (Table 5). Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents are available from the HIV/AIDS Treatment Information Service (http://www.hivatis.org).

The current goal of antiretroviral therapy is to reduce viral load to undetectable levels and maintain such remission without interruption. Evidence suggests that the therapies suppress replication but do not eradicate HIV from all parts of the body, particularly lymphoid tissue and the brain. Not all patients who initiate antiretroviral therapy respond. The lack of clinical response is likely explained by problems with adherence, suboptimal antiretroviral treatment potency, and genetic mutation of HIV strains (18). Many patients experience substantial side effects, and it is not uncommon for changes to be made in antiretroviral drug regimens because of such side effects. Adverse effects include lipodystrophy (fat redistribution syndromes), hyperlipidemia, nephrotoxicity, bone marrow suppression, neuropathy, and elevation of glucose to possibly diabetes mellitus–causing levels (19). Patients often experience nausea, diarrhea, sleep disturbances, and rashes. The cost of antiretroviral drugs alone is about $12,000 per year for a single individual, and the long-term health consequences of these agents are not known.

Adherence is of utmost concern with antiretroviral treatment because the regimens are so unforgiving; even minor deviations from the prescribed regimen can result in viral resistance and permanent loss of efficacy for existing medications. Studies of antiretroviral treatment continue to indicate that near-perfect adherence is needed to adequately repress viral replication. The potential implications of nonadherence are troubling, as evidenced by a study that found a primary viral resistance rate to antiretrovirals of 16.3% among a cohort of recently infected individuals (20). This study documented what was earlier considered a theoretical concern—namely that persons newly infected with HIV may carry viral strains already resistant to available antiretroviral agents, indicating transmission of resistant viral strains from persons who were taking nonsuppressive multiple drug therapy or who were nonadherent to treatment (21).

As the U.S. HIV epidemic spreads increasingly among disadvantaged persons with limited resources who may have multiple comorbid disorders, significantly more psychosocial stressors, and less access to ongoing primary or mental health care, these individuals are at risk of not receiving the recommended treatment for HIV infection. Services for HIV patients must balance medical interventions with the emotional, economic, and social supports required for good quality of life and prevention of further transmission.

1. Impact of HIV on the CNS

Clinical evidence for direct infection of the CNS by HIV emerged in the mid-1980s, when patients began to survive their presenting opportunistic infections but went on to develop neuropsychiatric syndromes that could not be attributed to CNS opportunistic infections or neoplasms. Additional evidence included signs of neurocognitive impairment in adults, loss or arrest of developmental milestones in children, ability to culture HIV from CSF, neuropathological lesions of the brain at autopsy, and abnormalities observed through brain imaging techniques, including cerebral atrophy.

HIV invades the CNS early in the course of infection, entering by way of macrophages, which along with microglial cells are largely responsible for HIV replication within the CNS. While HIV does not infect neurons in the CNS, it causes neuronal death by other mechanisms. It is hypothesized that HIV infection of microglial cells in the CNS causes the elaboration of neurotoxins that, in turn, cause neuronal damage (22, 23). Neuronal dysfunction usually takes place at a slow rate, and it is not clear whether the immune system plays a role in keeping HIV in the CNS under control (24). Some researchers believe that high systemic viral load may "drive" neurological disease (25), but there is converging evidence that the CNS compartment differs from that of the peripheral bloodstream, with independent viral evolution/mutation (leading to viral resistance) and different viral load decay kinetics (26, 27).

Major unanswered questions remain about the natural history of HIV in the CNS and whether current antiretroviral treatment regimens penetrate the blood-brain barrier sufficiently to reduce viral replication to the levels seen in the systemic circulation. Neuroprotective agents, immune modulators that increase macrophage activity within the CNS, and vaccines that boost immune response rather than prevent infection are all potential additional strategies to address neuropsychiatric syndromes.

2. Clinical syndromes

HIV infection can lead to neuropsychiatric syndromes that can occur at various stages of infection. Clinicians need to be aware of this possibility when evaluating new patients and observing changes in the patients whom they treat (28). Symptomatic HIV infection of the brain generally affects cognitive and motor functioning. Subtle neuropsychological impairment may be found in 22%–30% of otherwise asymptomatic patients with HIV infection (29, 30); these findings may or may not have functional significance. There is ample evidence for HIV causing the disorders HIV-associated dementia and HIV-associated minor cognitive motor disorder. HIV can affect other areas of the nervous system, causing syndromes such as painful sensory peripheral neuropathy or vacuolar myelopathy of the dorsolateral columns of the spinal cord. There are limited data in support of HIV infection of the CNS resulting in syndromes such as psychosis (31) or mania (32–34).

What separates HIV-associated dementia and HIV-associated minor cognitive motor disorder from the less severe cognitive changes seen in some HIV patients are the significance and duration of the functional deficits (Table 6, Table 7). HIV-associated minor cognitive motor disorder is a less severe disorder than HIV-associated dementia but does not necessarily progress to HIV-associated dementia (36). HIV-associated minor cognitive motor disorder is important to diagnose and treat, since it is thought to involve neuronal cell dysfunction rather than actual cell death, as seen in HIV-associated dementia. Both HIV-associated minor cognitive motor disorder and HIV-associated dementia are independent risk factors that decrease survival among patients with HIV infection (37, 38).

3. HIV-associated dementia

In contrast to Alzheimer's disease, which is a cortical dementia, HIV-associated dementia is classified as a subcortical dementia. HIV-associated dementia can produce different combinations of a clinical triad of progressive cognitive decline, motor dysfunction, and behavioral abnormalities. Symptoms commonly found in HIV-associated dementia include psychomotor slowing, decreased speed of information processing, impaired verbal memory and learning efficiency, and, later on, impairment in executive functioning. Behavioral manifestations vary throughout the range of HIV-related neurocognitive disorders, ranging from apathy to psychosis.

While the prevalence rate for HIV-associated dementia was estimated in the past to be 15%–20% of all AIDS patients (39), the incidence rate for HIV-associated dementia may be affected by the use of potent combination therapies. One report from the Multicenter AIDS Cohort Study (40) demonstrated declines of at least 50% in the incidence of HIV-associated dementia and CNS opportunistic complications (e.g., toxoplasmosis and primary CNS lymphoma) since the introduction of combination antiretroviral treatment in 1996. A second report has estimated that the incidence of HIV-associated dementia decreased from 21.1/1000 person-years in 1990–1992 to 14.7/1000 person-years in 1996–1997 (40). On the other hand, one group found that for patients who received combination antiretroviral treatment, the proportion of HIV-associated dementia as a percentage of all AIDS-defining illnesses rose from 4.4% to 6.5% between 1995 and 1997 (41). This shift in the rate of HIV-associated dementia is thought to reflect the decrease in rates of other AIDS-defining conditions, thereby leading to the relative rise in HIV-associated dementia cases.

4. Other psychiatric syndromes

Because HIV affects subcortical areas of the brain, it has been postulated that HIV may cause syndromes relating to mood and psychosis. New-onset psychosis and mania in HIV-infected patients tend to present at later stages of HIV disease and often occur in association with cognitive motor impairment. Lyketsos and colleagues (34) have described HIV-infected patients with so-called AIDS mania who present at advanced stages of HIV infection but generally have no family or personal history of mood disorder and have higher rates of comorbid dementia. They hypothesized that mania in this context is directly caused by HIV brain infection. Mijch and colleagues (32) conducted a prospective case-control study to test the hypothesis put forward by Lyketsos et al. In their study of 19 HIV patients with secondary mania, they found that treatment with zidovudine, which is known to penetrate the blood-brain barrier well, provided a protective effect against the development of mania. In addition, they found the incidence rate of HIV-associated dementia in the subjects with mania to be significantly greater than in HIV subjects without mania.

New-onset psychotic symptoms have been reported in HIV-positive individuals in the absence of medical/iatrogenic causes or concurrent substance abuse (42, 43). One case-control study systematically examined patients with HIV infection that predated the onset of psychosis (31). In this study, the psychotic subjects had significantly higher rates of past stimulant and sedative-hypnotic abuse and higher mortality at follow-up. While the study was limited by a sample size of 20, the authors postulated that direct effects of HIV infection on the brain could be one possible cause of new-onset psychosis in their subjects.

5. Differential diagnosis of neuropsychiatric syndromes

Differential diagnosis of an acute change in mental status includes but is not limited to delirium. Delirium occurs frequently in the medically ill and is more likely when a patient's illness is more severe. Estimates of rates of delirium in HIV patients range from 43% to greater than 65% in late-stage AIDS (44–46). Definition and management of the syndrome of delirium is well described in the APA Practice Guideline for the Treatment of Patients With Delirium (47; included in this volume). Identification of the delirious state and intervention to correct underlying causes reduces morbidity and mortality. In persons with HIV infection, the most common causes are iatrogenic and psychoactive-substance-induced toxicity, infection, neoplasms, and metabolic disturbances. Some antiretroviral medications can cause delirium (e.g., zidovudine at high doses [48] or efavirenz [49]) (Table 8).

The term "HIV encephalopathy" is occasionally used to refer to acute-onset cognitive deficits in adults, but its definition and usage vary. A wide range of conditions that primarily involve the CNS needs to be considered within the psychiatric differential diagnosis, since these conditions may present with psychiatric symptoms or cause psychiatric syndromes including psychosis (with or without an affective component) and mood episodes (mania, hypomania, depression) (51) (Table 9). The same concerns exist for medications commonly used to treat conditions associated with HIV infection (Table 10).

In adults and children with HIV infection, changes in mental status or the emergence of new psychiatric or cognitive disorders requires ruling out treatable and reversible causes; medical causes are of increasing concern if CD4 counts are low or viral load has begun to rise. Psychiatrists should consider adding assessments of basic immune function and viral load, CSF examination, and brain imaging studies to the standard medical workup of new- or acute-onset psychiatric syndromes for patients with or at high risk for HIV infection (Table 11).

6. Pediatric HIV/AIDS syndromes

To date, the proportion of children born with HIV who survive until the age of 9 is approximately 50%, but antiretroviral interventions will increase the number of infected youth who enter adolescence. HIV-related symptoms may develop at any age, but a prospective collaborative study found that only 10% of children were symptomatic before the onset of an AIDS-defining illness (53).

Certain clinical presentations characterized by lymphadenopathy, parotitis, skin diseases, and recurrent respiratory tract infections are associated with longer survival, while lymphoid interstitial pneumonitis and thrombocytopenia form an intermediate survival group. The worst prognosis is associated with bacterial infections, progressive neurological disease, anemia, and fevers (54).

HIV infection that occurs at the time of birth rather than early in gestation is thought to be associated with a better prognosis. While at any given time many HIV-infected children may not experience significant HIV-related medical morbidity, their overall health outcome may be compromised by the conditions of poverty.

The impact of HIV on the developing nervous system of children is more significant than on the developed adult nervous system, and certain cognitive deficits may occur in some infected youth. The term "dementia" is not commonly used to describe cognitive deficits in children by pediatricians or child psychiatrists, who refer to this condition as either HIV-associated progressive encephalopathy or HIV encephalopathy. Nonetheless, "dementia due to HIV disease" in children is specifically mentioned in DSM-IV (p. 148).

HIV-associated progressive encephalopathy in children is characterized by a triad of symptoms: impaired brain growth, progressive motor dysfunction, and loss or plateau of developmental milestones (55). Progressive encephalopathy needs to be distinguished from mental retardation secondary to other causes, such as maternal drug addiction and prematurity, which can be determined only by longitudinal assessment. Despite the general fact that progressive encephalopathy is observed in the context of immunosuppression, markers of immunologic functioning (e.g., CD4 count) do not correlate with degree of neurocognitive impairment (54). The prevalence rate of progressive encephalopathy in a cohort of 128 HIV-infected children was 21% during a mean follow-up period of 24 months. Progressive encephalopathy was the first AIDS-defining condition in 67% of the group, and mean survival after diagnosis was 14 months (56).

Although many children with HIV are considered to be asymptomatic, numerous studies document at least some cognitive and language delays (57). In a sample of 36 HIV-infected children who were less than 10 years old, brain abnormalities detected by means of computerized tomography scans were significantly correlated with receptive and expressive language deficits, with expressive language more severely impaired than receptive language among those children with progressive encephalopathy (58). In addition, visual motor deficits are common and may be correlated with disease progression (59).

Since early in the HIV epidemic, researchers have studied the prevalence of psychiatric disorders in persons with HIV infection (60–63). Often these psychiatric disorders predated HIV infection or occurred during the course of living with the disease; they are not necessarily attributable to neuropathic effects of HIV. Psychiatric illness is generally related to poorer functioning and quality of life as well as increased use of HIV-related hospital services (64). A study conducted by researchers in California found that depression was associated with shorter survival times in men with HIV infection (65).

Prevalence rates of psychiatric disorders reported in published studies vary widely. In general, higher rates of psychiatric disorders are seen in later stages of HIV infection and are reported in studies that assess patients receiving care in HIV medical or psychiatric clinics rather than community-based samples (66). On one extreme, recent data from the national, multisite HIV/AIDS Mental Health Services Demonstration Program revealed high rates of depression (60%), dysthymic disorder (25%), and anxiety disorders (25%) among persons seeking HIV-related mental health services in the public sector (67). The study found high rates of comorbid substance use disorders, with nearly 50% of all patients also having a diagnosis of alcohol or drug dependence. These higher rates are most likely linked to characteristics of the population studied: HIV-positive individuals voluntarily seeking psychiatric care, a population that may be more reflective of patients receiving care from community mental health clinics. In contrast, prevalence studies in selected community-based samples have found much lower rates of psychiatric disorders, such as rates of major depressive disorder in the 4%–14% range (68–73).