Patients With Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome

Overview

Human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) are prevalent in disenfranchised populations, including substance users, men-who-have-sex-with-men (MSM), sex workers, ethnic minorities, and the seriously mentally ill, who all have particular difficulty advocating for and accessing adequate care. Not only is HIV infection more prevalent among the mentally ill, but psychiatric illnesses are more prevalent in those who are HIV-positive. Patients with personality disorders are also over-represented in the HIV-positive population, likely because certain traits (e.g., impulsivity, reckless disregard for safety, affective instability, or chronic feelings of emptiness) can predispose persons to risky behavior and to HIV infection.

As recently as the 1990s, HIV infection was a terminal illness. However, the advent of highly active antiretroviral therapy (HAART) has made HIV a manageable, chronic illness for many, although sometimes associated with a high medication side-effect burden. A new cohort of aging patients with HIV infection, a range of cognitive difficulties, and chronic diseases not necessarily related to HIV itself, is emerging, despite (or because of) improved overall survival. Despite much progress, complacency, stigma, secrecy, and shame continue to interfere with HIV detection. Culture, lifestyle, and socioeconomic barriers to prevention and to appropriate HIV care persist.

HIV is a blood-borne, sexually transmitted retrovirus that contains RNA as its genetic material and the enzyme reverse transcriptase, which facilitates the (reverse) transcription of RNA to double-stranded DNA in infected human cells. This virion-derived DNA moves to the host cell nucleus, where it randomly integrates into host chromosomes, catalyzed by the virion-encoded enzyme, integrase. Once within the host chromosome, the pro-viral DNA can remain inactive (latent), or it can express a range of genetic activity, including functional virus production. Such now-functional viruses can go on to infect other cells, preferentially the CD4 subpopulation of T-lymphocytes, thereby causing severe (primarily cell-mediated) immune dysfunction for which the virus and the resulting syndrome were named. Immunodeficiency, a predilection for certain opportunistic infections, and AIDS-defining conditions correlate with a decline in CD4 lymphocyte count ( Table 30-1 ). This infection cycle repeats billions of times, the host mounts an immune response, and a set point (or dynamic equilibrium) is eventually reached. The set point varies from person to person, and it has been found to be of prognostic significance. Notably, the virus also invades the central nervous system (CNS) early, possibly within hours to days of the initial infection.

Although the science behind HIV infection and its treatment is changing at a rapid pace, the general tenets of this chapter should provide a consistent framework for the safe and comprehensive psychiatric evaluation and care of adults at risk for, or infected with, HIV/AIDS. Four general questions help set the context for such an evaluation: At what stage of HIV infection is the patient in terms of symptomatic disease and CD4 lymphocyte count? Is there evidence of HIV-associated CNS infection? Does the patient have a pre-morbid psychiatric history? How did the patient become infected with HIV? The important implications of the first three questions might seem more obvious and should be clear by the completion of the chapter. The fourth question is often a highly personal story, one that reveals the patient as a person. The answer to this question foreshadows how the patient will relate to illness and to medical care. This knowledge informs not only the psychiatrist's evaluation but also the patient's individualized treatment and management plans.

Epidemiology

Despite the existence of effective therapies, HIV/AIDS remains a terminal illness in much of the world; it cuts across all ages and socioeconomic groups, each with specific characteristics and considerations. The reported global prevalence of HIV has increased from 33.3 million in 2010 to 36.7 million in 2015. Women make up half of the infected adults worldwide, and roughly 1.8 million children younger than 15 years are infected.

There has been a gradual decrease in the incidence of new infections since a peak in 1998, with a 2015 incidence of roughly 2.1 million, with 150,000 of those new cases diagnosed in children younger than 15 years. This incidence is only partially offset by the (declining) total number of AIDS deaths (1.1 million in 2015), which means the number of persons living with HIV will continue to rise, although the prevalence (measured over a growing global population) has stabilized. Eastern and Southern Africa remains the most heavily infected region, accounting for 52% of all people living with HIV, for 43% of all AIDS deaths, and for 46% of all new cases in 2015. Nonetheless, these percentages have declined dramatically since the 1990s.

In the United States, among the most heavily infected industrialized nations, more than 1.2 million people are infected with the virus, of whom over 150,000 (13%) are unaware of their status. The incidence of new infections is stable in the United States at about 50,000 per year. The advent of HAART in 1996 has decreased the incidence of AIDS onset and AIDS-related deaths, so more people in the United States are living with HIV infection than ever before.

HIV is an example of a concentrated epidemic, as the risk for contracting HIV is not evenly distributed across the population. A disproportionate number of the newly infected in the United States are ethnic and racial minorities (primarily Black and Hispanic; less so Asian and Pacific Islanders), and heterosexual women. However, outbreaks of other sexually transmitted illnesses (STIs) in gay men raise the specter of a possible HIV resurgence in this population and suggest that the success of HAART may have led to complacency and the resumption of unsafe sexual practices in MSM, to some degree fueled by the recreational use of methamphetamine (crystal meth). Indeed, in 2011, the majority of new HIV diagnoses in the United States were among MSM (in all but one state), and the incidence among this group increased by 12% from 2008 to 2010. Furthermore, unprotected anal sex at least once in the past 12 months increased from 48% in 2005 to 57% in 2011. Up to 30% of patients with HIV disease are also infected with hepatitis C virus (HCV). These co-infected patients are rather different from HIV mono-infected patients with regard to risk factors and psychiatric illnesses; most patients have acquired HCV from injection drug use, which is the main mode of transmission for HCV.

Medications for HIV Infection

Early treatment is now the gold standard in patients with HIV. ART initiation at the time of diagnosis, regardless of CD4 count, is recommended to reduce clinically relevant morbidity and mortality related to, and unrelated to, HIV/AIDS. In a large multi-site, multi-continent study known as the “START study,” early treatment was shown to significantly reduce the risk of serious AIDS-related events, serious non-AIDS-related events, or death from any cause, compared with a deferred-treatment initiation arm, in which subjects were not treated until the CD4 count dropped below 350. Since 2012, the United States Department of Health and Human Services (DHHS) guidelines have recommended immediate ART initiation; with publication of the START study, the WHO has adopted the recommendation of ART for all as well.

Goals of antiretroviral therapy are to achieve sustained virologic suppression of HIV, recover immune function (for which the surrogate marker is CD4 T lymphocyte cell numbers), and thereby reduce HIV-associated morbidity and mortality and reduce community transmission of HIV. There are currently six FDA-approved classes of antiretroviral medications: nucleoside reverse transcriptase inhibitors (NRTIs); non-nucleoside reverse transcriptase inhibitors (NNRTIs); protease inhibitors (PIs); integrase strand transfer inhibitors (INSTIs); entry inhibitors; and fusion inhibitors. As described earlier, the complex process leading to successful viral replication and propagation involves several steps. Drugs target various stages of the HIV replication cycle: in the first four classes mentioned, they interfere with viral replication inside infected host cells; the latter two classes prevent viral entry into the host cell. Antiretroviral medications are used in combinations, typically three agents from more than one class. Single-drug therapy is ineffective because of the rapid development of resistance to that agent and in turn, to an entire class of medications. Similarly, incomplete adherence to a multi-drug combination regimen allows HIV-1 to continue replicating, again allowing for mutation to occur and class-wide resistance to develop, thus limiting the prospects for further effective treatment. Therefore, the impression of importance of adherence to medications and engagement of patients in therapy is critical for treatment success.

The United States DHHS provides recommendations for the treatment-naive patient, of which first-line consists of two NRTIs plus either an INSTI or ritonavir-boosted PI. Of these, there are currently three one-pill once-daily options; several studies and a meta-analysis have shown better adherence in populations receiving once-daily regimens ( Table 30-2 ).

HIV Infection and the Central Nervous System

Within days of the initial infection, the virus is transported to the brain by monocytes that then differentiate into macrophages. These infected but not dead macrophages may be activated randomly, leading over time to excessive secretion of normal inflammatory substances and cell death without neuronal infection. That is, HIV infection causes neuronal destruction without infecting neurons. The CNS appears to be an independent reservoir of HIV replication; CSF viral load does not consistently correlate with plasma levels. HIV in the CNS might also have different characteristics, such as mutations with increased viral resistance or neurotoxicity, than those of the peripherally observed virus. Current antiretrovirals have variable blood–brain barrier penetrance, they may be less potent inhibitors of viral replication within the CNS, and some are themselves neurotoxic. The optimal antiretroviral drug regimen to combat HIV in the brain remains to be determined, but peripheral suppression of viral replication will need to be coupled with neuroprotection. New therapies might target regulatory human genes involved in viral replication, the identification and exploitation of brain HIV-inhibitory factors, and the enhancement of intrinsic brain defenses that favor neuroprotective, as opposed to neurotoxic, responses to the virus.

HIV has a predilection for subcortical structures, such as the hippocampus and basal ganglia, with lower concentrations in the cerebellum and mid-frontal cortices. This distribution, further differentiation of viral burden within particular basal ganglia regions, and concomitant structural changes in the brain (including ventricular enlargement, hippocampal atrophy, decreased basal ganglia volume, and white matter lesions), might explain the more characteristic cognitive and behavioral impairments associated with HIV infection of the CNS, as well as the sensitivity of patients with HIV to the extrapyramidal symptoms (EPS) of certain psychiatric medications. These types of lesions in the base of the skull are better visualized by brain magnetic resonance imaging (MRI) than by computed tomography (CT) scanning.

When evaluating neurocognitive impairment in the HIV-positive patient, HIV infection of the CNS should always be a diagnosis of exclusion, made only after a thorough investigation of other possible etiologies for neurocognitive impairment, especially if symptoms are new or of acute onset. Opportunistic infection, neoplasm, other systemic illness, medication side effects, drug–drug interactions, use of recreational drugs, withdrawal syndromes, and metabolic and nutritional derangements should be considered. Primary psychiatric disease should be at the bottom of the list, especially if there is not a significant pre-infection history.

Although neuropsychologic testing might not be specific, it helps to localize and quantify impairments. Recommended neuropsychological tests include an HIV-specific test battery based on measures found by the AIDS Clinical Trials Group (ACTG) and the Multicenter AIDS Cohort Study to be sensitive to HIV-related cognitive deficits. These measures include Trail Making A and B, WAIS-R (Wechsler Adult Intelligence Scale—Revised) digit span and digit symbol, grooved pegboard, finger tapping, Stroop color and word test, FAS test of verbal fluency, Odd Man Out test, and computer-based measures of complex reaction time. Other measures are added as clinically indicated. Test battery times less than 60 minutes are less likely to produce patient fatigue, which confounds test interpretation and creates significant patient frustration or humiliation. Despite these recommendations, there is no ideal test, and it is important to keep in mind that mild deficits on testing can have significant functional consequences.

HIV-Associated Neurocognitive Disorders (HAND)

HAND encompasses three conditions, including HIV-associated dementia (HAD), HIV-associated mild neurocognitive disorder (MND), and asymptomatic neurocognitive impairment (ANI). HAND presents with executive dysfunction, memory impairment, attention deficits, and poor impulse control, and can be associated with motor dysfunction including bradykinesia, loss of coordination and gait imbalance. These conditions are all diagnosed using neuropsychological testing and functional status assessments, and are thought to affect 15% to 55% of HIV-positive individuals.

Differential Diagnosis of Psychiatric Distress

Psychiatric symptoms are common in the HIV-infected population and can reach a level of severity to meet criteria for Diagnostic and Statistical Manual for Mental Disorders , 5th edition (DSM-5) disorders. Or, as with neurocognitive impairments, psychiatric symptoms may be sub-syndromal; underlying causes should be identified and reversed when possible, although it might still be necessary to treat the psychiatric symptoms ( Table 30-3 ).