National Academies Press: OpenBook

AIDS and Behavior: An Integrated Approach (1994)

Chapter: 4 DISEASE PROGRESSION AND INTERVENTION

« Previous: 3 UNDERSTANDING THE DETERMINANTS OF HIV RISK BEHAVIOR
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

4
Disease Progression and Intervention

Although every effort must be made to prevent new transmission of HIV, it is equally important to diagnose, treat, and care adequately for people who already are infected. This chapter presents an overview of findings from research on the pathogenesis and disease progression of HIV/AIDS relevant to mental health and substance abuse and on possible interventions to control the infection's effects. This research, which has developed quickly over the past decade, ranges from basic molecular and cellular biology to clinical pathology to social psychology, and has recently provided some important clues about the relationships between HIV, the brain, and behavior, and most importantly, about their interactive nature. In so doing, this research demonstrates the need for cross-disciplinary approaches to HIV prevention and intervention.

Chief interactions reviewed here include: (1) HIV infection of the brain and the effects HIV has on the central nervous system; (2) effects of interactions among HIV infection, substance use, and mental illness and the unique medical care and treatment issues associated with such interactions; and (3) the relationship between psychosocial factors and HIV infection for individuals with the disease, as well as for their loved ones and caregivers.

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

THE RELATIONSHIP BETWEEN HIV AND THE CENTRAL NERVOUS SYSTEM

EFFECTS OF HIV ON THE CENTRAL NERVOUS SYSTEM: DEFINING THE ISSUES

A group of organic nervous system disorders may complicate the course of HIV infection and may result directly from HIV infection. HIV-associated conditions affecting both the central nervous system (CNS) and peripheral nervous system (PNS) are common and result in considerable morbidity and mortality. They can be classified in a number of ways. Many can be considered secondary complications of HIV infection, resulting from opportunistic infections or systemic organ dysfunction that follows from immune deficiency induced by HIV infection. Among the major CNS complications of AIDS are cerebral toxoplasmosis, primary CNS lymphoma (an opportunistic neoplasm associated with Blymphocyte infection by Epstein-Barr virus), cryptococcal meningitis, and progressive multifocal leukoencephalopathy (PML) caused by the JC virus (for reviews, see Brew et al., 1988; Johnson, 1994; Koppel, 1992; Price, 1994; Price and Worley, 1994; Snider et al., 1983).

Other conditions likely relate more directly to HIV infection itself, rather than to an additional opportunistic infection or systemic organ dysfunction. These can be considered primary nervous system complications of HIV. While their pathogenesis is not yet clearly understood, they are thought to be sequelae of interactions among HIV, the immune system, and various components of the nervous system. These include some unusual disorders complicating the early phases of HIV infection as well as common conditions occurring later. In the earliest phase of infection, a number of syndromes have been described, including mild meningitis with headache. However, while these syndromes are usually absent or mild, it is likely that in the course of spreading throughout the lymphatic system, HIV also reaches the brain at this time within infected lymphocytes, but without causing any clinical symptoms or signs.

Later in the course of systemic HIV infection, patients may develop so-called ''aseptic" meningitis that presumably is caused by HIV infection of the membranes surrounding the brain. They also may experience a peripheral neuropathy causing pain in the feet. However, of particular relevance to the issues of this report, HIV-infected persons also are susceptible late in the course of

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

systemic infection to an affliction that impairs brain function in a stereotyped manner. This syndrome, referred to as AIDS dementia complex (ADC), as well as by a variety of other terms (HIV dementia, HIV-associated cognitive-motor complex), likely is caused by HIV itself and is mediated either by toxic effects of certain molecules coded by the viral genome or by cell-coded products, principally cytokines (American Academy of Neurology AIDS Task Force, 1991; Price, 1994; Price and Perry, 1994).

ADC can be a source of protracted and severe disability, modifying and markedly diminishing the quality of remaining life, reducing enjoyment of work and daily life, depriving the patient of social and intellectual pleasures, and requiring emotionally and financially costly care needs. In its mild form, ADC syndrome slows intellectual processing, blunts concentration, and impairs rapid and fine motor control. When more severe, it causes truly devastating dementia that reduces the patient to a shell of his or her former self—dulling the personality, impairing walking, and eventually leaving the victim bedridden, incontinent, and mute (Navia, Cho, Petito, et al., 1986; Navia, Jordan, and Price, 1986; Price and Sidtis, 1992). This neurological syndrome was in fact recognized early in the course of the AIDS epidemic by U.S. clinicians in the epicenters of the disease on both the east and west coasts. However, because ADC was first noted in the setting of a novel infection, it took some time to recognize and refine its clinical features, to describe precisely its natural history and pathogenesis, and subsequently to approach and evaluate its prevention and treatment. Eventually, a clearer picture began to emerge, with speculation focusing on a possible relationship between AIDS and human cytomegalovirus (CMV) opportunistic infection of the CNS (Snider et al., 1983). However, after further clarification of the features of the syndrome, with its pathology and the clinical-pathological correlations, CMV infection no longer seemed to provide an adequate explanation (Navia, Cho, Petito, et al., 1986). Because this syndrome was unlike any known complications of immunosuppression previously described in other populations, such as cancer and transplant patients, speculation turned to the same putative agent that caused AIDS itself; and when HIV was then identified (as LAV and HTLV-III) research began to test whether this virus might not only cause immunosuppression, but might more directly cause the AIDS dementia complex (Price et al., 1988).

The search for the virus in the brains of ADC patients soon revealed evidence of high amounts of proviral DNA in some (Shaw et al., 1985). At the same time, molecular studies of HIV showed

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

that it was related to visna virus, a prototype slow or lentivirus type of retrovirus well known to cause CNS infection and disease in sheep (Gonda et al., 1985). Further reports documented early exposure of the brain (or at least cerebrospinal fluid, or CSF) to HIV and also identified active infection of the brain late in the disease (Brenneman et al., 1988; Dreyer et al., 1990; Gabuzda et al., 1986; Koenig et al., 1986; Wiley et al., 1986). These rapid developments led to the initial concept that ADC was the result of CNS HIV infection and thus that the virus infected not only the immune system but the brain as well. However, more detailed subsequent work indicated that the cause and pathogenesis of ADC are not so straightforward, but rather involve a complex interaction among the virus, the immune system, and the CNS (Epstein and Gendelman, 1993; Price et al., 1988; Price, 1994; Spencer and Price, 1993).

STAGING AND CELLULAR SITES OF CENTRAL NERVOUS SYSTEM INFECTION IN AIDS DEMENTIA COMPLEX

The core features of the AIDS dementia complex have now been well characterized, and a descriptive staging system, useful to provide a common vocabulary for both clinical practice and clinical investigation, has been developed (see Price, 1994; Sidtis, 1994). Nonetheless, more precise defining characteristics still must be developed in order to standardize clinical trials. Likewise, evaluation methodologies have been developed, but more precise definition of abnormalities is still needed. Standard measures are needed to interpret and quantify neuroimaging studies (MRI and CT scanning), CSF profiles, and neuropsychological test results (Price and Sidtis, 1990; Sidtis, 1994). Defining markers for the degree of viral infection will also be important. Together these will aid the more precise characterization of the natural history and epidemiology of ADC. Likewise, these methods should improve evaluation of the efficacy of prevention and treatment, as new agents to reduce the viral burden and to interrupt neurotoxic processes are brought into the clinic. These are all important clinical issues in reducing the disease burden associated with established HIV infection.

The character of HIV infection of the CNS is not yet fully understood. It appears to vary in its profile during the course of systemic HIV infection. This variability relates to the importance of the immune system in suppressing HIV replication early and then failing to suppress replication late in infection. Additionally,

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

changes in the virus, both with respect to predominant cell tropism and virulence may be important. Thus, from the very early period of infection, the CNS is exposed to HIV presumably through the traffic of infected cells from the bloodstream. This traffic may continue throughout infection, perhaps with diminished intensity during the phase of clinical latency, but increasing again in the later (AIDS) phase of infection (Spencer and Price, 1993). Thus, a number of studies have shown early invasion of the CNS and early local host immune responses in the CSF. A critical question remaining to be answered is whether the virus then persists in the CNS in latent form or as an indolent infection that is asymptomatic. If it can remain latent, then research must discover which cells might harbor the proviral DNA: microglia, astrocytes, or other CNS cells.

If the virus is latent in, for example, astrocytes, is that important for the subsequent course of infection in the CNS and for disease production? Or is the course of later infection dominated not by the opportunity for infection, but rather by the factors that control replication? Thus, the later stage of systemic infection is dominated by high-titer viremia with enhanced probability of viral entry into the CNS; this late entry might far overshadow earlier events. Subsequent replication of HIV within the CNS appears to relate to loss of immune control, determined by the effects of systemic infection on the immune system (O'Brien, 1994).

MECHANISMS FOR CAUSING SYMPTOMS

The characteristic symptoms and signs of ADC have led to classification of this syndrome among the subcortical dementias, a group that includes Parkinson's disease, progressive supranuclear palsy, hydrocephalus, and other conditions in which cognitive dysfunction is associated with damage to nerve cell nuclei and white matter in the diencephalon rather than cerebral cortex. AIDS dementia complex shares with these disorders a slowing of thinking and concentration along with motor dysfunction, in contrast to the cortical dementias such as Alzheimer's disease and Creutzfeldt-Jacob disease, in which amnesia, aphasia, apraxia, and the like are more characteristic. Understanding the nature and physiology of brain dysfunction in AIDS patients has both practical and theoretical importance. A clear characterization of ADC should capture its salient features and set it off from other conditions. The lack of such a distinction, and the unfortunate evolving usage of the term dementia, which is most often applied to Alzheimer's

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

disease and multi-infarct dementia, has already resulted in some confusion in both the definition of AIDS dementia complex and the criteria for diagnosis, with an inappropriate effort to apply criteria that relate more to those other dementing conditions than to ADC itself (American Academy of Neurology AIDS Task Force, 1991). The emphasis on symptoms of cognitive decline, as opposed to motor slowing and other features more prominent in subcortical diseases, also has confused efforts to develop neuropsychological test batteries for ADC and other subcortical syndromes.

Understanding why patients develop the changes in thinking and behavior characteristic of ADC holds lessons for cortical-subcortical relations and for the abnormalities noted in other subcortical dementias. Positron emission tomography (PET) studies of brain glucose metabolism have shown a curious enhanced metabolism of diencephalic regions compared with cortex (Rottenberg et al., 1987). The reason for this seemingly paradoxical finding remains to be explained (paradoxical because reduced metabolism might have been anticipated on the basis of symptoms, and because these structures appear to be more susceptible to HIV infection than cortex).

MECHANISMS OF CENTRAL NERVOUS SYSTEM INJURY

A complex picture emerges from pathological studies indicating that productive HIV infection in the brain occurs in cells of bone marrow origin (monocyte-macrophages and microglia) rather than in the neuroectodermal cells (nerve cells and other supporting cells in the brain such as oligodendrocytes and astrocytes) that perform the specialized work of the CNS. The extent of infection often appears greater than the degree of brain dysfunction, at least until the later stages of ADC, suggesting that the pathological effects of infection are somehow attenuated despite high levels of CNS infection. Early studies of CSF, and more recent studies of brains taken at autopsy, indicate better correlation between CNS dysfunction and markers of immune activation than with infection. Taken together, these observations suggest that the virus indirectly injures the brain rather than directly killing or infecting nerve cells. This distinguishes HIV from other viral infections of the brain caused by poliovirus or herpes simplex virus. Poliovirus, the most intensely studied human virus of an earlier era, directly infects motor neurons and causes the death of these cells, producing paralysis. By contrast, in the case of

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

HIV, the link between the viral genome and CNS dysfunction is far less direct. The virus itself does not appear to kill nerve cells, and its presence in the CNS early in infection appears to be benign. Later neuronal dysfunction bears an uncertain relationship to the CNS virus load (Masliah et al., 1994; Price, 1994).

Gradually, a coherent picture is emerging of initiation of brain injury by HIV infection, which is mediated by immunopathological processes in which cell-coded signals result in brain injury. Such processes might be involved in many infectious diseases, but are less prominent because they are overshadowed by the direct neurotoxic effects of the foreign organism and because they are short-lived. HIV infection differs because the virus is not, in itself, capable of damaging neuroectodermal cells directly, and because infection is so protracted. The regulation and profile of immune responses are also profoundly disturbed, with alterations or loss of normal feedback inhibition loops.

In particular, interest has recently focused on the neurotoxic properties of gene products from the HIV virus itself, and from HIV-infected immune cells. The HIV coat glycoprotein, gp 120, allows HIV to bind to macrophages and may in turn be released by infected cells, resulting in neuronal damage and death (Giulian, Vaca, and Noonan, 1990; Pulliam et al., 1991). Extremely low concentrations of gp 120 increase intraneuronal calcium, which causes injury and death in cell and tissue culture systems (Brenneman et al., 1988; Dreyer et al., 1990). Moreover, injection of gp 120 into the brain ventricles of rats induces misshapen hippocampal pyramidal cell processes associated with behavioral abnormalities (Hill and Brenneman, 1990; Panlilio et al., 1990; Pert et al., 1989). The HIV nuclear protein tat was found to be neurotoxic for glioma and neuroblastoma cell lines (derived from brain support cells) in culture and to mice in vivo (Sabatier et al., 1991). The significance of these observations is being explored.

Recent experiments have raised other possibilities to account for HIV-elicited neurotoxicity. Astrocytes, another critical class of supporting cells in the nervous system, produce growth and survival factors that are essential for normal brain function (see Lu et al., 1991). In a culture of hippocampal cells, the peptide neuromodulator VIP (vasoactive intestinal peptide) prevents gp 120-induced neuronal toxicity (Brenneman et al., 1988). VIP is known to act on astrocytes, releasing factors necessary for neuronal survival and neurite outgrowth (Festoff, Rao, and Brenneman, 1990; Russell et al., 1990).

Parallel studies focusing on immune system cells, including

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

macrophages and microglia, suggest that these infected cells in the nervous system release unidentified toxic factors that kill chick, rodent, and human neurons in vitro (Giulian, Vaca, and Noonan, 1990; Pulliam et al., 1991). The toxic agents may represent gp 120 itself, a fragment thereof, or other molecules released in response to gp 120. The precise relationships between HIV, immune cells, toxic factors, and neuronal damage remain to be elucidated.

While causal mechanisms have not been traced, some final common pathways of neuronal damage are being explored. Activation of calcium channels (both those that respond to voltage and to so-called NMDA receptors, which respond to excitatory amino acids) appears necessary for HIV-induced neuronal injury. Extensive study suggests that gp 120 sensitizes neurons to the toxic effects of NMDA receptor stimulation (for review, see Lipton, 1992). In aggregate, studies suggest that agents blocking gp 120 or NMDA receptors might ameliorate the neuropathological effects of HIV infection. Consequently, pharmacologic agents that have little influence on HIV itself may nevertheless represent important therapeutic adjuncts in the treatment of HIV-induced neurologic disease. It may be possible to treat symptoms of ADC with a different class of agents that block virus replication itself.

The activation of certain immune reactions late in infection has likewise led to studies of the mechanisms of damage to the immune system. These have centered principally around effects of cytokine upregulation. Some putative cell-coded neurotoxins are quinolinic acid (an endogenous excitatory amino acid), nitric oxide, Tumor Necrosis Factor, NMDA agonists, and arachidonic acid metabolites (Benos et al., 1994, Brenneman et al., 1988; Dawson et al., 1993; Epstein and Gendelman, 1993; Garry and Koch, 1992; Guilian, Vaca, and Noonan, 1990; Heyes et al., 1991; Heyes, Saito, Crowley, et al., 1992; Kaiser, Offerman, and Lipton, 1990; Lipton, 1991, 1992, 1994; Masliah et al., 1994; Pulliam et al., 1991; Toggas et al., 1994; Wahl et al., 1989; Werner et al., 1991; Wesselingh et al., 1993). A picture is emerging of multiple toxins acting in concert as part of dysregulated cytokine cascades triggered by immune responses or by viral signals, together disrupting or destroying neuronal function in selected brain regions. However, these processes are only beginning to come into focus and require considerable investigation to clarify both relevance and mechanisms.

Understanding these pathogenic mechanisms has great potential for treating ADC patients, using not only methods that interfere with the virus, but also employing strategies directed at interrupting some of these toxic processes. Indeed, these considerations

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

underlie some of the approaches now being taken to treat the AIDS dementia complex, including treatment protocols using nimodipine, a calcium channel blocker that can prevent gp 120-induced neuronal death in vitro, and pentoxyphilline, an antagonist of Tumor Necrosis Factor.

Some of the critical areas regarding the pathogenesis of the ADC and others that remain to be addressed include: identifying the precise molecular and cellular cascades through which gp 120, tat, and other HIV peptides contribute to AIDS neuropathology; identifying which peptides or receptors constitute appropriate pharmacologic targets; determining if such new agents can be safely combined with antiviral therapy to enhance clinical efficacy; identifying the mechanisms through which monocytoid cells, including macrophages and microglia, elicit neuropathology; revealing the identity of the mediating molecules and how they are regulated at the transcriptional, translational, and post-translational levels; determining how HIV infection itself evokes monocytoid-induced neuropathology; determining whether inhibition of astrocyte growth and trophic factors mediates AIDS neuropathology; identifying the mechanisms through which gp 120 and VIP putatively interact; defining a monocytoid-astrocyte-neuron cascade in AIDS brain pathology; determing whether elevated intracellular calcium accounts for all the neuropathology in AIDS; characterizing the relationship of voltage-gated and NMDA-receptor-channel calcium influx in causing nerve cell damage; and determining whether gp 120 and NMDA receptors directly interact and, if so, what the mechanisms are that foster calcium influx. Based on the foregoing, the next step is to see if new agents to prevent the neurologic sequelae of AIDS can be designed and tested in culture models, experimental animals, and the clinic, and to determine if there are any animal models of predictive value, other than non-human primates.

These questions may seem daunting, but studies on the AIDS dementia complex have evolved in a short period of time from a primitive state of empirical observations to experiments with possible direct therapeutic implications, not only for ADC, but also for other neurological and psychiatric diseases, especially those mediated by viruses or immune dysfunction. Therapeutic trials are currently under way to evaluate whether pharmacological interruption of the neurotoxic processes involved in ADC might alleviate neurological incapacity.

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
SIGNIFICANCE OF AIDS DEMENTIA COMPLEX FOR OTHER CENTRAL NERVOUS SYSTEM DISORDERS

Research on the AIDS dementia complex and CNS HIV infection has importance not only for understanding the nature and course of HIV infection, but also more generally for suggesting mechanisms involved in other infectious, immunological, and neurodegenerative diseases. The early penetration of the blood-brain barrier by HIV, the local immune response detected in the spinal fluid, and the subsequent active replication of HIV in the brain late in infection hold clues regarding the CNS ecology of HIV. How does the virus reach the brain? In lymphocytes or monocytes, or as free virus? Does it remain latent in the brain, providing a reservoir and refuge from chemotherapy? How does it later commence active replication in the brain, and what is the importance of genetic variants of the virus with enhanced capacity to replicate in the brain?

The pathogenesis of ADC involves processes that have been observed in animal models (usually of viral diseases studied as models of degenerative disorders), but that have received less attention in human diseases with a known viral cause. Unlike most other human infections, HIV infection is characterized by long latency, a seeming lack of direct nerve cell destruction in the absence of immunosuppression (which HIV first induces before then affecting the brain), and the principally indirect mechanisms of brain injury alluded to earlier. In one sense, HIV infection can be considered as an acquired genetic disease in which a tightly regulated foreign genome is transplanted into an unwelcoming host where it then causes gradual and protracted disease. The mechanisms involved in resultant neurodegeneration are likely shared by other infections, and even other degenerative and genetic conditions. Research into the mechanisms of brain injury caused by HIV infection will likely produce lessons for these other conditions, and therapies that interrupt neurotoxic processes may well be applicable to other diseases. Studies of AIDS therefore may have very real and very important spillover effects into other disease areas.

The mechanisms involved in HIV-induced brain injury and ADC are also involved in other diseases. While protracted in time and perhaps altered in its profile, cytokine activation is part of other infectious, immunological, and neurodegenerative diseases. Intermediate and final pathways of neuronal dysfunction and death are likely shared between ADC and other viral encephalitides,

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

multiple sclerosis, postinfectious encephalomyelitis, paraneoplastic diseases, Alzheimer's disease, and even schizophrenia. Shared mechanisms may be involved whenever an abnormal gene provokes immune responses with potential to include neurotoxic responses.

CLINICAL SIGNIFICANCE OF AIDS DEMENTIA COMPLEX

The primary motivation to study ADC and HIV infection of the CNS is to treat the disability they cause. While the prevalence of ADC is still somewhat uncertain, it remains a significant complication of HIV infection, and its severe impact on the lives of patients makes it an important target of prevention and treatment. As opportunistic infections are increasingly prevented by antibiotic prophylaxis, an increase in the prevalence of ADC threatens, although such a trend has not appeared in national statistics. In evaluating antiretroviral and other therapies, the study of ADC may also prove useful, because its symptoms are a continuous variable (so small changes can be measured) and reversible. Evaluation of treatment efficacy therefore does not require monitoring of sporadic events such as opportunistic infections, as in most current AIDS clinical trials, but rather the measurement of improved performance on tests of brain function.

INTERACTIONS AMONG HIV, SUBSTANCE USE, AND MENTAL ILLNESS

The second type of interaction among HIV, the brain, and behavior relates to the unique issues associated with multiple diagnoses, that is diagnosis of any combination of HIV, drug or alcohol abuse, and mental illness. This kind of multiple diagnosis is not uncommon, and it likely affects disease progression as well as treatment strategies. It is vitally important to recognize the interactive nature of HIV infection, substance use and abuse, and mental illness in order to appropriately intervene. This, too, requires a cross-disciplinary approach.

ALCOHOL AND THE IMMUNE SYSTEM

Drinking alcohol to excess has been shown to cause damage to the immune system (Kruger and Jerrells, 1992). It therefore seems reasonable to assume that alcohol consumption in significant amounts may also render an individual more vulnerable to HIV infection

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

and facilitate the transition from HIV infection to AIDS. However, this assumption has not been substantiated by the relatively few studies to date that have examined the relationships among alcohol, the immune system, and HIV infection. Although research suggests that alcohol generally does play a role in immune system functioning, alcohol may not advance the progression of AIDS among the HIV positive (Kaslow et al., 1989; Ostrow et al., 1990).

The effects of alcohol on the immune system and on HIV infection likely depend on a person's drinking habits. The amount, duration, and frequency of consumption, as well as the presence of liver disease may play a role. Moreover, because many of the effects of alcohol on the immune system are reversible, the relationship between the timing of alcohol consumption and the stage of HIV infection may influence alcohol's effect.

Alcohol directly alters the defensive cells, or phagocytes, that digest and degrade viruses. Alcohol also apparently suppresses the production of two important cytokines that assist phagocytes in their defensive actions. Together, these suggest that alcohol may increase the susceptibility of phagocytes to initial infection, impairing their ability to eliminate the virus in the early stages of infection, and thus increasing their potential to function as reservoirs for HIV (Kruger and Jerrells, 1992).

Alcohol also reduces the number of T-cells in the spleen, lymph modes, thymus, and blood (Jerrells, Smith, and Eckardt, 1990; Saad and Jerrells, 1991). In addition, remaining cells may be more susceptible to initial infection upon contact. Alcohol-induced loss of cells in the immune system may accelerate the onset of clinical manifestations among HIV-infected people, but research on this issue has been inconclusive. Although it is clear that excessive alcohol consumption can impair cell-mediated immunity, this has not translated into accelerated clinical progression of HIV to AIDS in reports to date (Isaki and Gordis, 1993; Kaslow et al., 1989). The precise relationship between alcohol use and HIV/AIDS remains to be elucidated.

DRUG USE AND HIV/AIDS

The large number of drug injectors already infected with HIV pose a significant challenge to the medical care system to recognize and treat the varied clinical manifestations of HIV infection and disease in this highrisk population. Treatment of drug users who are at risk for or already infected with HIV is complicated by

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

several factors: the fact that the clinical course of HIV infection may have special characteristics among drug injectors, the existence of complex medical and psychosocial comorbidities, and the often tenuous relationship between drug users and the health care system. Although a significant body of research has been conducted on clinical aspects of HIV disease and its management among drug users, a number of key research areas require further examination.

Natural History of HIV Infection Among Drug Users

Most studies that have described rates of progression to AIDS or clinical manifestations of HIV disease in drug users have been performed among cohorts in which the date of primary HIV infection is unknown (Des Jarlais et al., 1987; Selwyn, Alcabes, Hartel, et al., 1992). These cohorts have tended to include many with advanced HIV infection at the time of study. Although several large cohorts already exist in the United States and Europe with greater proportions of subjects with known incident HIV infection (Munoz et al., 1992; Rezza et al., 1989; Willocks et al., 1990), natural history studies of HIV disease in seroincident cohorts must continue to be conducted in the future.

Changes in the spectrum of HIV disease over time, such as the emergence or disappearance of AIDS-related illnesses among drug users as a result of medical interventions or other differences, have yet to be charted. Such changes have been noted in male homosexual populations, but these patterns must be studied over time among drug users as well (Hoover et al., 1993; Moore et al., 1992).

Clinical aspects and outcomes of certain conditions that are common in HIV-seronegative drug users (Cherubin and Sapira, 1993) but may occur more frequently in HIV-infected drug users (Mientjes et al., 1992; Selwyn, Alcabes, Hartel, et al., 1992) also demand elucidation. These include endocarditis, cellulitis or abscess, pneumonia, bacteremia, and other pyogenic bacterial infections, especially in relation to CD4 counts and degree of immunosuppression (comparing endocarditis in patients in early and late HIV infection, regarding severity, infecting organisms, and outcome, among other factors).

Preliminary data suggest that the occurrence of certain clinical conditions, such as bacterial infections and tuberculosis (TB) may hasten disease progression in HIV-infected drug users (Alcabes, Schoenbaum, and Klein, 1993; Farizo et al., 1992; Mientjes et al.,

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

1992; Selwyn, Alcabes, Hartel, et al., 1992; Stoneburner et al., 1988; Willocks et al., 1992). However, the prognostic importance of these conditions has yet to be fully determined. Additionally, there is a need for further epidemiologic and clinical study of tuberculosis among HIV-infected drug users, to address primary versus reactivation tuberculosis (Daley et al., 1992; Hopewell, 1992; Selwyn, Hartel, Lewis, et al., 1989), cutaneous anergy (failure to respond to TB skin tests despite infection with the TB bacterium) (Moreno et al., 1993; Selwyn, Sckell, Alcabes, et al., 1992), the observed preponderance of tuberculosis outside the lung among drug users (Braun et al., 1990), and the relationship of demographic and social variables to the observed highrisk of tuberculosis among drug users (Reichman, Felton, and Edsall, 1979). The relationships among drug use (particularly drug smoking), the physical and social context of illicit drug use, and the risk of bacterial pneumonia and tuberculosis should be clarified (Caiffa et al., 1993; CDC, 1991a).

Given the relationship between HIV infection and co-infection with other organisms, the evidence of high levels of both hepatitis B and hepatitis C infection among drug users, and the key importance of liver disease in this population, it also will be important to clarify further the clinical expression and outcome of hepatitis C infection in co-infected groups (Donahue et al., 1991; Esteban et al., 1989; Haverkos and Lange, 1990; Kreek, 1983; Novick et al., 1988; Stimmel, Vernace, and Schaffner, 1975; van den Hoek et al., 1990).

Moreover, the prognostic importance of standard laboratory markers used in the assessment of HIV disease state among drug users (e.g., CD4+ T-lymphocyte subsets, Beta-2-microglobulin, neopterin, and hematologic indices) will be important to reassess, given evidence that some markers may not be as useful in drug users as in other populations. While substantial data already exist in this area, the issue can still bear further scrutiny (Alcabes et al., 1994; Chaisson et al., 1991; Davenny et al., 1990; Fernandez-Cruz et al., 1990; Munoz et al., 1992; Rezza et al., 1989; Selwyn, Alcabes, Hartel, et al., 1992).

The role of drug and alcohol use in the progression of HIV disease has received much interest in the past, but it still has not been studied definitively with respect to the hypotheses that the immunosuppressive or immunostimulatory effects of psychoactive drug use might hasten the progression of HIV infection (Kaslow et al., 1989; Rezza et al., 1989; van Griensven et al., 1990; Weber et al., 1990).

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Medical Care for HIV-Infected Drug Users

As HIV infection increasingly has become a treatable condition, the focus has shifted appropriately from observational studies of disease progression toward medical interventions to alter its course. Intervention studies will have increasing relevance for drug users, regarding not only clinical management but also health services access and utilization. Here, too, however, a number of areas remain to be explored more fully.

Pharmacokinetic and other pharmacologic studies involving drugs of abuse and medications used for the treatment of HIV-related disease, as well as prescribed opioids such as methadone used to treat opiate addiction, will help determine whether interactions have potential clinical significance. Studies from the pre-AIDS era documented clinically important pharmacologic interactions between methadone and rifampin (used to treat tuberculosis), phenytoin (a treatment for epilepsy), and other medications (Kreek, 1983; Kreek et al., 1976; Tong et al., 1981). Preliminary studies with certain HIV-related medications have been performed, involving methadone and zidovudine (AZT), and more recently, rifabutin, with suggestive but inconclusive results (Sawyer et al., 1993; Schwartz et al., 1992). With the increasing number of medications continually being added to the standard therapeutic regimens of HIV-infected patients, it will be even more important in the future to assess these agents pharmacologically in relation to psychoactive drugs, both prescribed and over-the-counter drugs.

As noted above, the high background prevalence of liver disease may complicate the treatment of drug injectors, because many therapeutic agents used for the management of HIV disease (e.g., a wide range of antibiotics and antiretroviral agents) have potential liver toxicities, especially among those with preexisting liver damage. Systematic studies of drug toxicity, side effects, and the ability to tolerate standard therapeutic regimens among HIV-infected drug users will increase in importance.

Because most of the therapies used for HIV infection and related conditions (e.g., tuberculosis) require long-term medical regimens, often involving multiple medications, the levels of adherence among drug users in a variety of treatment settings must be examined. In particular, the relationship between active substance abuse and adherence to medical care is a critical question requiring further study. Preliminary data in this area are somewhat conflicting; some studies suggest that substance abuse may interfere with effective use of health services, while others have found that adherence

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

in a medical program oriented toward drug injectors is no lower among those actively using drugs (O'Connor et al., 1992; Samet et al., 1992; Selwyn, Feingold, Iezza, et al., 1989; Selwyn et al., 1993). Interventions to promote adherence to medical care among drug users will affect both clinical research and program evaluation.

Drug injectors as a group are likely to have a high lifetime prevalence of depression, anxiety, personality disorder, and other psychiatric diagnoses (Batki, 1990a; Rounsaville et al., 1991). In addition, underlying psychopathology, especially depression, was identified as a predictive factor for persistent risk-taking behavior among drug users in one study that linked continued needle sharing to depression, and certain psychiatric disorders may be associated with lack of engagement with or follow-up with medical care for HIV infection among drug users (Batki, 1990a). The comorbidity of drug abuse and psychiatric disorders is an important area for further study, to examine both the mental health determinants of risk-taking as well as the tendency to seek or avoid health care, and to develop strategies for enhancing engagement of follow-up with care. More fundamentally, these themes highlight the importance of pursuing a research and clinical agenda that brings together mental health services, drug abuse treatment, and medical care for HIV.

Among persons with HIV infection, drug users as a group are the least likely to have sustained and consistent contacts with the health care system, especially in the areas of primary care and preventive services. They are more likely to rely on acute care services, if at all, with episodic use of emergency rooms for acute HIV-related illnesses and medical complications of injection drug use (O'Connor et al., 1992). Compared with men who have sex with men, drug injectors are less likely to receive antiretroviral therapy for HIV infection within the health care system (Moore, Hidalgo, and Sugland, 1991; Rosenberg et al., 1991; Stein et al., 1991). In spite of these findings, however, it has been clearly demonstrated that drug users can achieve high levels of adherence to HIV-related medical care, including chronic, complex outpatient regimens, when these services have been made accessible and geared specifically to their needs. Several paradigms have been developed for the provision of HIV-related medical services to drug injectors, including on-site services within methadone programs and prisons, programs linking drug treatment and primary care centers, special hospital-based services, and outreach programs such as mobile medical van services linked to needle exchange (Altice

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

et al., 1992; Altice et al., 1993; Glaser and Greifinger, 1993; O'Connor et al., 1992; Samet et al., 1992; Selwyn, Feingold, Iezza, et al., 1989; Selwyn et al., 1993). Health planning, policy, and basic health services and evaluation research must assess more formally the effectiveness of these and other models of care for drug users with or at risk of HIV infection. These questions also hold relevance for basic policy issues concerning the integration of substance abuse treatment into mainstream medical education and practice (Lewis et al., 1987), a trend that has been stimulated in part by the AIDS epidemic (National Commission on AIDS, 1991b).

INTERVENTIONS FOR THE SERIOUSLY MENTALLY ILL

The convergence of psychiatric disorders, substance abuse, and HIV among those who are also severely mentally ill raises difficult questions about appropriate treatment, similar to issues related to treatment of injection drug users. For example, possible toxic reactions between antipsychotic and anti-HIV medications, and perhaps even antinarcotic medications, require further investigation. Moreover, little if anything is yet known about HIV disease progression among the seriously mentally ill. Given what has already been learned about the interactions of the virus and the CNS, it is possible that unique manifestations occur among people already suffering brain disorders. Yet this area remains remarkably understudied.

A larger problem is the general failure of mental health and drug abuse service providers and medical professionals to adequately address treatment issues for dual- and triple-diagnosis patients, who, because they are perceived as difficult and complicated, often are ''extruded" by treatment systems (Fine, 1993). Greater sensitivity and understanding about the mental and physical health problems and needs of this population, and a willingness to address them in managed treatment, is essential both to preventing transmission of HIV among them and to treating those already infected.

THE RELATIONSHIP BETWEEN PSYCHOSOCIAL FACTORS AND HIV INFECTION

The final type of HIV, brain, and behavior interaction addressed in this chapter is the relationship between HIV infection and certain psychiatric disorders, behavioral states, or reactions. For example, concern about HIV infection can lead to anxiety or depression.

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

The stress of coping with the illness is not confined to the person infected, but also encompasses those who care for him or her. The management of HIV infection carries both diagnostic and therapeutic implications that may not be directly related to HIV infection per se. It may be difficult to distinguish depression or anxiety from the AIDS dementia complex, because many symptoms overlap. The treatment is quite different—the dementia complex may respond to drugs that inhibit HIV replication, while depression and anxiety are more likely to respond to antidepressant and antianxiety medications—and so this distinction is clinically important. Since these conditions may also coexist, and the treatments themselves may affect CNS function, clinical management of both domains overlaps.

The bidirectional relationship between psychosocial factors and HIV infection can influence disease progression and the ability to effectively treat related symptoms. These phenomena primarily have been informed by two types of research: psychoneuroimmunology and psychosocial research on coping and caregiving.

PSYCHONEUROIMMUNOLOGY

The neurobiology of AIDS involves the possible influence of the nervous system on immune function and how both respond to HIV infection. In the context of HIV/AIDS, psychoneuroimmunology is the study of how mental states might modify immune defenses and even viral replication within the immune system. Depression and other mental states may have an impact on the immune system through the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, and other pathways. Stress and other nervous system perturbations may alter immune function in both animal models and humans. The complex interactions among HIV infection, immune function, and mental state have been a major theme of AIDS-related research, particularly at NIMH. Although much has been learned about the effects of HIV on psychosocial factors, less is known about the effects of psychosocial factors on HIV. The few studies undertaken so far to examine this relationship show, variously, no effects of stressors (stressful life events) on illness progression (Kessler et al., 1991) and only an indirect relationship (Blaney et al., 1990). Further investigation is needed on when and how such effects may occur (Folkman, 1993).

The direct importance of mental states on progression of HIV infection is uncertain at best, and there is no clear evidence that one or another mental disorder or state either retards or accelerates

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

progression. Two studies published simultaneously in December 1993 reached opposite conclusions about whether depression accelerated the decline of CD4+ lymphocyte counts.

Data from the Multicenter AIDS Cohort Study in Baltimore, on the one hand, revealed no evidence that depressive symptoms independently led to worse outcomes in HIV infections. Researchers concluded that symptom reports, CD4 counts, and socioeconomic status were confounding variables. Moreover, they concluded that because depression appears to be etiologically related to AIDS-related physical symptoms, those symptoms are probably direct confounders (Lyketsos et al., 1993).

Data from the San Francisco Men's Health Study, on the other hand, found that overall depression and affective depression predicted a more rapid decline in CD4 lymphocyte counts, and that this association was not attributable to baseline physical differences. Researchers were unable to identify the actual mechanism operating, but ruled out the possibility that the association was due to perceived somatic symptoms or to differences in substance abuse. However, they, too, concluded that the association between depression and disease progression may have been confounded by the impact of both on neurological disease (Burack et al., 1993). Neither study showed a significant effect of depressive symptoms or major depression on whether an HIV-positive subject was classified as having advanced AIDS or on overall mortality. The issue of the direction of the relationship between depression and HIV disease progression—to the extent that there actually is one—remains unresolved.

It is probable that CNS modulation of immune defenses is relatively minor in relation to the overwhelming influence of the virus and other determinants on the type and potency of immune responses to HIV. The bidirectional relationship between the CNS and the immune system, including nerve cell attachments to immune organs and how those may modify immune events, is nonetheless likely to influence the dynamics of HIV infection, although measuring such effects in HIV-infected persons may be extremely difficult because of the influence of cofactors, such as substance abuse, among some such individuals.

COPING WITH HIV/AIDS

For most people, the psychological impact of AIDS begins before an HIV test has even been taken, and for those who are HIV positive, it continues to change as the disease progresses. Research

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

in the fields of psychology, psychiatry, epidemiology, anthropology, and sociology is contributing to a knowledge and understanding of the many psychosocial aspects of HIV/AIDS and has helped to point the way toward developing appropriate interventions.

The very decision to undergo an HIV test involves a calculation of costs and benefits on the part of the individual. The most significant costs include confronting the possibility of a positive test result and fearing a breach of confidentiality (Coates, Stall, Kegeles, et al., 1988). At the same time, the benefits of testing include clarifying one's HIV status and being motivated to change one's behavior in positive ways (Siegel et al., 1989). The difficulty of making this cost-benefit calculation is evident in the fact that many people, maybe as many as 28 percent, do not obtain the result of their tests (Catania, Kegeles, and Coates, 1990; McCusker et al., 1988; Peterson et al., 1990). Among those who do learn the results of their HIV test, research has found mixed reactions. Some studies have shown a significant increase in psychiatric symptoms, including depression, among those who were notified of their serostatus, compared with those who did not receive the test results (McCusker et al., 1988; Ostrow et al., 1989). Other research, however, found no such relationship, leading the authors to hypothesize that for some people, the stress of not knowing one's serostatus may be as significant as that of knowing (Perry et al., 1990).

After learning that they are HIV positive, most people "manage" and "tolerate"—as opposed to "master" or "eliminate''—the psychological changes that result (Folkman, 1993). This involves employing strategies of coping and social support, which are different at different stages of the disease. Studies of asymptomatic HIV-positive people suggest that "avoidant coping"—screening out the negative implications and focusing instead on the positive—does not protect them from distress (Joseph et al., 1990; Nicholson and Long, 1990; Rabkin et al., 1990; Storosum, Van Den Boom, and Beauzekom, 1990). This finding is consistent with the general literature on coping. But it is not yet known whether HIV-related situations inherently are more stressful than others, or if avoidant coping itself is inherently maladaptive (Folkman, 1993). Cognitive coping strategies, however, such as positive reinterpretation, gaining a sense of control over events, and effecting positive changes in daily life, seem to promote psychological well-being throughout the course of the disease (Hart et al., 1990; Rabkin et al., 1991; Storosum, Van Den Boom, and Beauzekom, 1990).

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

Although a number of studies have focused on the psychiatric implications of HIV/AIDS, they have not been able to determine whether psychiatric disorder is an effect of HIV or existed prior to HIV. For example, among gay men psychiatric morbidity rates are high relative to the general population regardless of HIV serostatus. This may be due to the fact that these men have to deal with a host of psychological issues related to their sexual status (Atkinson et al., 1988; Tross et al., 1987; Williams et al., 1991). This finding suggests the need to understand how the context of HIV affects psychiatric symptoms among gay men, that is, what disclosure and recognition of both being gay and having HIV may mean.

There is evidence that, at least among men, strong social support—from friends or family—is related to maintaining hope and morale throughout the progression of the disease (Rabkin et al., 1991). Unlike among heterosexuals, among gay men who are HIV-positive but not yet diagnosed with AIDS, peers are more significant than family (Hays et al., 1990). But this reverses once AIDS is diagnosed. The reluctance of many gay men to turn to family may be due to larger issues of being gay, as well as to more immediate issues of being geographically distant from family and having the strong support of the gay community in close proximity.

Once a person is diagnosed with AIDS, the psychological and psychiatric implications of having HIV are presumed to gain in importance and to take precedence over other considerations (Weitz, 1989). However, research on anxiety and depression has produced essentially mixed findings. Some studies have found more depression among symptomatic and asymptomatic HIV-positive individuals than among those who are AIDS-diagnosed (Chuang et al., 1989), while others have found higher rates of depression and anxiety among diagnosed men than among untested, seronegative, seropositive-asymptomatic, or seropositive-symptomatic men (Folkman et al., 1993).

These mixed findings suggest that people adjust to living with AIDS by adopting cognitive coping strategies. Some consciously adopt strategies for minimizing stress, anxiety, and depression, while others achieve it through the actions involved in living with AIDS, such as investigating new drug therapies, educating oneself about the illness, taking control of one's legal and financial affairs, and planning the end of one's life (Folkman et al., 1993; Namir et al., 1987).

Intervention research related to ameliorating the psychosocial effects of HIV/AIDS is still underdeveloped. The few studies undertaken to date have focused on maintaining positive morale

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

(Fawzy, Namir, and Wolcott, 1989) and on reducing stress and depression (Folkman et al., 1993; Perry et al., 1991) among people with HIV/AIDS. Nearly all of the research on coping to date, however, has focused on gay men. Much remains to be learned about how people from various gender, racial/ethnic, and cultural groups, and with different risk factors, such as injection drug users, cope with their own and others' HIV status, including not only general psychological strategies, but also motivation or resistance to adherence to medical treatment and its implications for disease progression. Future interventions should be brief, be theory-based, be effective in teaching coping skills, include techniques for maintaining such skills, and produce manuals that enable replication of the interventions elsewhere (Folkman, 1993).

In addition to the HIV-infected person, AIDS has psychosocial implications for those around him or her. One of these is bereavement—the experience of grief and loss of a loved one. Research on bereavement suggests that it is affected by the meaning of the death involved. In the case of AIDS, death occurs at a relatively young age, it afflicts the communities in which survivors participate—raising fears about their own risks vis-à-vis the disease, and it afflicts numerous members of the same community (Folkman, 1993). For gay men and injection drug users, AIDS-related loss is cumulative (McKusick and Hilliard, 1991; Neugebauer et al., 1992). Some of the psychological implications of such loss include traumatic stress response, demoralization, and sleep problems (Martin, 1988). Social support, to some degree, can help people recover from grief (Lennon, Martin, and Dean, 1990; Wortman, Silver, and Kessler, in press). Current research by Folkman and colleagues at the Center for AIDS Prevention Studies in San Francisco is addressing whether social support is a factor in successful coping with bereavement over time (Folkman, 1993).

CAREGIVING FOR PEOPLE WITH HIV/AIDS

The psychosocial impact of HIV/AIDS is experienced not only by people with the disease, but also by those who care for them. A large body of literature consistently associates caregiving with psychological and physical morbidity (e.g., Cantor, 1983; Gallo, 1990; Pruchno, Kleban, and Michaels, 1990), but this literature focuses primarily on caregiving among the frail elderly, which is usually performed by a female relative. Little is known about caregiving factors among men who are likely to be the caregivers of gay men with AIDS.

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

At this point in time, AIDS is a chronic, episodic, debilitating, and eventually fatal disease. Increasingly, AIDS care is being provided as much (if not more so) in the patient's home and by a lover or family member as it is in hospitals by trained professionals. A broad appreciation of the AIDS caregiving issue is central to an understanding of the complexity of providing high-quality, cost-effective support to those infected. But little is yet known about either the characteristics of people giving care—formally or informally—or the psychosocial implications of their work.

Informal Caregivers

So far, there has been no systematic research on the demographic and other characteristics of people providing informal AIDS care, that is people without professional training providing physical and psychological care in a home setting. However, data from recent studies (Folkman, Chesney, and Christopher-Richards, 1994; Turner, Catania, and Gagnon, 1994) suggest that AIDS caregivers of gay men do not fit the traditional caregiver profile—an older female family member who belongs to an age cohort with more prevalent chronic illnesses and who has been socialized to be nurturing. AIDS caregivers tend to be younger, just as likely male as female, and are diverse with respect to sexual orientation and relationship to the care recipient. In major cities, for example, 26 percent of AIDS caregivers are heterosexual men, 42 percent are heterosexual women, 25 percent are gay or bisexual men, and 7 percent are lesbian or bisexual women (Turner, Catania, and Gagnon, 1994). The caregiving role is thus highly non-normative for a large proportion of AIDS caregivers.

Many caregivers are the lovers or partners of gay men with AIDS. Some are HIV-positive themselves. Usually they are young, and instead of building relationships (an appropriate developmental task at this stage of life), they are preparing for loss. The relationships between these caregivers and their ill partners are usually informal and not legally sanctioned. Moreover, since AIDS is stigmatized, caregiving is frequently hidden from the family and community (Herek, 1990; McCann and Wadsworth, 1992; Raveis and Siegel, 1991). This situation also affects older gay persons with AIDS, for whom access to family care may be especially restricted. They are more likely to be geographically separated from their families, they are generally less able to rely on parents for caregiving support, and they are more often faced with ruptured family ties because of their sexual orientation (Turner and

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

Pearlin, 1989). For injection drug users on the other hand, evidence from one study suggests families do play a significant role in AIDS caregiving (Schiller, Crystal, and Karus, 1990).

Recent investigations into the mental health effects of AIDS caregiving has concentrated on the population of gay men providing care to their partners (Raveis and Siegel, 1991; Turner, 1988). This likely reflects the fact that gay men constituted over 60 percent of AIDS cases reported between 1981 and 1993 (CDC, 1994) and that one-third to one-half of gay men with AIDS are cared for by gay peers (McCann and Wadsworth, 1992; Turner, Catania, and Gagnon, 1994). However, other populations of caregivers (e.g., those who care for HIV-infected drug users) also deserve attention. While some of the psychological implications for gay caregivers may be unique to their particular status vis-à-vis the epidemic, others probably are not.

Many caregivers are on call at all times and are intensely emotionally involved. At the same time, they may have never before given physical care to a seriously ill person and have never watched someone die. Therefore, caregivers are forced to learn a range of skills on the job, including technical tasks, such as properly administering medication and inserting and cleaning catheters, and emotional tasks, such as maintaining hope in the face of continued disease progression, providing a safe environment for the expression of fear and anger, and providing support while the care recipient is dying (Folkman, Chesney, and Christopher-Richards, 1994). It is not uncommon for caregivers to experience dysphoria—an emotional state of depression, anxiety, and restlessness (Folkman, Chesney, and Christopher-Richards, 1994). They must adjust to the partner's unpredictable illness progression, the shifting of responsibility from the person with AIDS to the caregiving partner, the stress of unexpected, temporary improvement in the partner's health, dealing with a virtually uncontrollable disease, role conflict fatigue, and concern about their own future and who will care for them if they are HIV positive.

Nevertheless, caregivers attempt to maintain positive morale all the while they are dealing with such difficult circumstances. Coping strategies include finding ways to create meaning in life, for example, by extending love through their caregiving, and savoring the ordinary, by taking pleasure in the acts of everyday life (Folkman, Chesney, and Christopher-Richards, 1994).

Parental caregivers are usually later-life families who are beyond the childrearing years and whose children have begun careers of their own. Very little is known about them and the

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

impact on families and parents of caring for an HIV-positive child (Mellins and Ehrhardt, 1993). Family history has been noted as an important factor in family caregiving patterns during the later years. A parent's sense of affection and obligation toward a gay son with AIDS is grounded in the family's history. It is affected both by structural factors, such as parent role and birth order, and social psychological factors, such as parent/child alliances and family members' perceptions of each other's personality. These factors are important for understanding how family members relate to one another when faced with a stressful event, such as a gay son acquiring AIDS, and how they then deal with their caregiving roles and responsibilities (Frierson, Lippman, and Johnson, 1987).

The important role of families in the care of people with AIDS has not yet been adequately recognized in the health care system, which for example still focuses on individual case management plans (Goeren, Wade, and Rodriguez, 1990). In order to design a truly comprehensive plan, a family case management model might be employed that would include family treatment (medical, nursing, and psychological) and family-focused clinical trials. Expanded training of health care providers is needed in order to incorporate such a family systems approach in the care of HIV-infected individuals.

Formal Caregivers: Health Care Professionals

As with informal caregivers, not much is yet known about formal caregivers. For the most part, research has focused on how health care workers deal with the stress and burnout of providing care to AIDS patients. Some of the most significant sources of stress include working with stigmatized clients, confronting one's own sexuality, and facing dying patients who are the same age as the caregivers. The most significant predictors of the dimensions of burnout are time pressure (emotional exhaustion), vague criteria of success (reduced personal accomplishment), and stress related to client behavior (depersonalization). Research has found that people who use confrontational coping strategies are reportedly less likely to suffer burnout.

Surprisingly, stress caused by death and dying of the client is not a significant predictor of burnout among AIDS caregivers, as it has not been for caregivers in the fields of oncology and geriatrics. The confrontation with death and dying instead seems to promote the personal growth of health care personnel and the sense of meaning in their lives (Kleiber et al., 1992).

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

Although stress experienced by HIV caregivers is reported in professional and lay articles, research has not included systematic documentation of the incidence and prevalence of physical, psychological, occupational, or interpersonal symptoms or disorders in health care professionals who devote a substantial amount of their clinical activities to patients with HIV illness (Silverman, 1993). Surveys have revealed that fear of contagion is a significant sentiment expressed by health care professionals resistant to providing AIDS care (Silverman, 1993). Anecdotal evidence of AIDS-related nightmares, psychological numbing, aversion to patients with HIV infection, and exhaustion among professionals providing AIDS-related health care also have been reported (Friedland, 1989; Shulman and Mantell, 1988; Silverman, 1993). These symptoms, together with others related to stress and depression, suggest that some caregivers might be experiencing a form of post-traumatic stress disorder. However, according to Silverman (1993), only one published psychiatry article has addressed this possibility (Horstman and McKusick, 1986).

The psychological and physical implications of AIDS caregiving for health professionals undoubtedly is affected by their attitude toward AIDS. Surveys among nurses, physicians, dentists, social workers, psychiatrists, and health profession students are notable for revealing a consistent aversion among caregivers to the HIV/AIDS disease, to patients and their lifestyles, and to caregiving work itself (Silverman, 1993).

Future Research on Caregiving

As HIV/AIDS is shifting from a seemingly immediate, fatal disease, to a more chronic (but still apparently fatal) syndrome, the roles and responsibilities of caregivers—both informal and formal—toward people with AIDS also will change. In order to provide the best possible circumstances for both provider and recipient of AIDS care, much more research must be conducted on the psychological and social factors involved at both ends of the relationship. For example, more information is needed about which particular aspects of social support and health are associated, how this association changes over time according to the stage of the disease, and the socioeconomic and cultural characteristics of those with HIV (Green, 1993).

More information is needed about the types of individuals who typically provide informal care to persons with AIDS, including their relationship to the patient, the characteristics of both patients

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

and caregivers that influence the acquisition and quality of informal care, the objective and subjective burden imposed by caregiving, and the impact of such burdens on the health and well-being of the caregivers (Turner, Catania, and Gagnon, 1994).

With respect to family caregivers, studying the characteristics that differentiate low-stress from high-stress families may enable professionals to develop interventions for high-stress families (Takigiku, Brubaker, and Hennon, 1993). It also will be important to include an examination of the special needs of families in which more than one member is HIV infected (Goeren, Wade, and Rodriguez, 1990).

In the particular case of parent caregivers of gay sons with AIDS, research should further develop contextual models of stress that take into account the family's ethos of affection/obligation, the unique meanings that families attach to the situations surrounding a gay son with AIDS, and how those might be influenced by gender, race/ethnicity, and the attitudes family members have toward homosexuality (Takigiku, Brubaker, and Hennon, 1993). Similar considerations should be applied to studies of caregiving among injection drug users and others.

In some instances, the parent caregiver of a person with AIDS also is HIV infected. This is frequently the situation in pediatric AIDS cases, approximately 85 percent of which result from vertical transmission (Susser et al., 1992). In these cases, caregiving is complicated by one's own illness. For example, studies have shown that HIV-positive parent caregivers are significantly more depressed and demoralized than HIV-negative parents (Susser et al., 1992). The particular needs of these parents should be identified and appropriate interventions should be developed.

With respect to formal caregiving, empirical research that can test hypotheses such as the existence of undiagnosed occupational, physical, and psychiatric morbidity related to HIV caregiving is needed. Moreover, research on stress among AIDS-related health care workers must move beyond the anecdotal and descriptive to theoretical and comparative perspectives that can locate the particular experience of AIDS caregiving within larger issues of professional stress and aversion to certain diseases and the people who suffer them. Adequate HIV/AIDS caregiving increasingly will require a deeper appreciation of the relationships between such things as social group dynamics and status and psychological and physical morbidity experienced both by people with HIV/AIDS and by their caregivers. A related issue worthy of study is the psychological and social consequences (including occupational stress)

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

of dealing with HIV/AIDS among outreach workers and service providers (Broadhead and Fox, 1993).

CONCLUSION AND RECOMMENDATIONS

CONCLUSION

Examining the interactions among HIV infection, the central nervous system, and psychosocial factors related to disease progression and intervention makes it apparent that, although crucial insights have been gained, a number of urgent questions remain. The gaps in knowledge identified in this chapter point the way for future research at the institutes charged with focusing on the interactions of brain and behavior. Any successful approach to the prevention, treatment, and management of AIDS—especially as it becomes a more chronic disease—must combine highly focused research in many disciplines with integrative, cross-disciplinary efforts that synthesize the biological and psychosocial to address questions that range from understanding the molecular mechanisms of nerve cell dysfunction to identifying the specific health care problems of those with multiple diagnoses.

RECOMMENDATIONS FOR DISEASE PROGRESSION AND INTERVENTION

4.1 The committee recommends that NIMH continue research on the pathogenesis of HIV infection of the brain, including the factors controlling virus replication such as local immune defenses and changes in the viral genome determining neuropathogenicity.

4.2 The committee recommends that NIMH continue research on the pathobiology of nervous system injury underlying the AIDS dementia complex, including the morphological, biochemical, and molecular basis of neuronal dysfunction related to viral and cellular gene expression.

4.3 The committee recommends that NIMH support collaborative studies of the prevention and treatment of the AIDS dementia complex and other central nervous system complications of HIV infection.

4.4 The committee recommends that NIAAA, NIDA, and NIMH continue supporting research on the development of animal models for examining the basic neurochemical and behavioral changes associated with HIV/AIDS.

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

4.5 The committee recommends that NIAAA, NIDA, and NIMH expand research on the natural history of HIV infection among various populations, including injection drug users, other substance abusers, and the seriously mentally ill.

4.6 The committee recommends that NIAAA, NIDA, and NIMH support research on the relationship between the medical consequences of substance abuse and related behaviors and the clinical expression of HIV among the drug-using population.

4.7 The committee recommends that NIAAA, NIDA, and NIMH support research at the intersection of AIDS treatment and clinical care for substance abusers, addressing, for example, how to treat HIV/AIDS in mental health and substance abuse treatment programs.

4.8 The committee recommends that NIAAA, NIDA, and NIMH collaborate on research to investigate interactions among psychotropic (including illicit) drugs, antinarcotic and anti-psychotic medications, and drugs used to treat HIV and opportunistic infections—for example, the effect of methadone on zidovudine (AZT)—including research on toxicities that might develop through such drug interactions.

4.9 The committee recommends that NIAAA, NIDA, and NIMH support more research on the neuropharmacology of anti-HIV medication.

The committee recommends that all relevant NIH institutes eliminate systemic barriers to the inclusion of injection drug users and other substance abusers in AIDS and AIDS-related clinical trials.

4.10 The committee recommends that NIAAA, NIDA, and NIMH support research on the utilization of health resources by people with AIDS, including substance abuse and mental health treatment programs. This research might include studies of the extent and manner in which the medical system acts (intentionally or not) to exclude drug users from care.

4.11 The committee recommends that NIAAA, NIDA, and NIMH support research on the relationship between adherence to HIV/AIDS medical treatment and disease progression among individuals from diverse gender, racial/ethnic, and cultural groups.

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×

4.13 The committee recommends that NIAAA, NIDA, and NIMH support research that integrates substance abuse and mental health treatment; in particular, demonstration projects for integrated multidisciplinary treatment systems that include mental health.

4.14 The committee recommends that NIMH support research on positive as well as negative consequences of HIV, for example, how people with AIDS and their caregivers maintain positive coping strategies in the face of the disease.

4.15 The committee recommends that NIAAA, NIDA, and NIMH support research on how families (broadly defined to include persons who consider themselves to be family through mutual commitment) from diverse racial/ethnic, socioeconomic, and sexual orientation backgrounds cope with the reality of having family members who are infected with HIV or have AIDS. Special attention should be given to patterns and consequences of caregiving in such families.

Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
This page in the original is blank.
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 124
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 125
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 126
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 127
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 128
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 129
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 130
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 131
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 132
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 133
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 134
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 135
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 136
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 137
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 138
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 139
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 140
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 141
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 142
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 143
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 144
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 145
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 146
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 147
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 148
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 149
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 150
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 151
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 152
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 153
Suggested Citation:"4 DISEASE PROGRESSION AND INTERVENTION." Institute of Medicine. 1994. AIDS and Behavior: An Integrated Approach. Washington, DC: The National Academies Press. doi: 10.17226/4770.
×
Page 154
Next: PART II MANAGING THE AIDS RESEARCH PROGRAMS AT NIAAA, NIDA, AND NIMH »
AIDS and Behavior: An Integrated Approach Get This Book
×
Buy Paperback | $95.00
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

HIV is spreading rapidly, and effective treatments continue to elude science. Preventive interventions are now our best defense against the epidemic—but they require a clear understanding of the behavioral and mental health aspects of HIV infection and AIDS.

AIDS and Behavior provides an update of what investigators in the biobehavioral, psychological, and social sciences have discovered recently about those aspects of the disease and offers specific recommendations for research directions and priorities.

This volume candidly discusses the sexual and drug-use behaviors that promote transmission of HIV and reports on the latest efforts to monitor the epidemic in its social contexts. The committee reviews new findings on how and why risky behaviors occur and efforts to develop strategies for changing such behaviors. The volume presents findings on the disease's progression and on the psychosocial impacts of HIV and AIDS, with a view toward intervention and improved caregiving.

AIDS and Behavior also evaluates the status of behavioral and prevention aspects of AIDS research at the National Institute of Mental Health, the National Institute on Drug Abuse, and the National Institute on Alcohol Abuse and Alcoholism.

The volume presents background on the three institutes; their recent reorganization; their research budgets, programs, and priorities; and other important details. The committee offers specific recommendations for the institutes concerning the balance between biomedical and behavioral investigations, adequacy of administrative structures, and other research management issues.

Anyone interested in the continuing quest for new knowledge on preventing HIV and AIDS will want to own this book: policymakers, researchers, research administrators, public health professionals, psychologists, AIDS advocates and service providers, faculty, and students.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!