Epidemiology

It is estimated that more than 36.7 million people are infected with HIV globally. In the United States the CDC estimated that 1,122,900 adults and adolescents were living with HIV at the end of 2015. Because of complex social and economic factors, African Americans and Hispanics/Latinos are disproportionally affected, with approximately 44% of HIV diagnoses in 2016 being African American and 25% being Hispanic/Latino. There is a higher geographical distribution of HIV diagnosis in US southern states, with 16.8 per 100,000 people in 2016. Alarmingly, it is estimated that approximately 51% of young individuals (aged 13 to 24) in the United States infected with HIV are unaware of the infection.

In 2017 the World Health Organization (WHO) estimated that 940,000 people died from HIV-related causes globally. Worldwide, in 2017, of the 36.9 million people (all ages) living with HIV, 35.1 million are adults, 18.2 million are women, and 1.8 million are children (<15 years). New HIV infections in 2017 totaled 1.8 million, with 1.6 million in adults and 180,000 in children (<15 years). Global AIDS deaths have continued to decline, totaling 940,000 in 2017; adult deaths were 830,000, whereas children (<15 years) totaled 110,000. For the United States, in 2015, 6465 people died from HIV disease, with 53% living in the southern United States. For 2016, in the United States, there were 39,782 new infections (with approximately 50% in the southern states); 26,570 were gay and bisexual men, 9578 were heterosexuals, and 3425 were individuals who inject drugs. Of those new infections, 14,740 were for ages 20 to 29, 9943 for ages 30 to 39, 6490 for ages 40 to 49, 4882 for ages 50 to 59, 1930 for ages 60 and older, and 1675 for ages 13 to 19.

Normal immunity

The immune system is complex and dynamic, comprising a multitude of components and subsystems, all of which interact continuously. The normal immune system has two main components, or lines of defense, against illness ( Fig. 34.1 ). The first is the innate, or inborn, immune system, which includes aspects such as the skin, the cilia and mucosal linings of the respiratory and digestive systems, the gastric fluids and enzymes of the stomach, natural killer cells, phagocyte cells, and the complement system. This innate component of the immune system keeps pathogens out of the body by creating barriers against them, by ejecting them, or by enveloping them and eliminating them. The second, the acquired component of the immune system, develops defenses against specific pathogens; it begins in utero and continues throughout life. It is the acquired (or antibody-based) immunity that is most pertinent to understanding HIV infection and its progression.

Main components of immunity.

Acquired immunity

Acquired immunity is divided into humoral and cell-mediated responses. Humoral immunity depends on the production of antibodies. This response is effective for disposing of free-floating or cell-surface pathogens. The cell-mediated response is required to destroy infected cells, those with intracellular pathogens. Cell-mediated immunity is essential for destroying pathogens responsible for the opportunistic infections and neoplasms that are associated with HIV infection. ^,

For the study of HIV pathology, it is important to consider three types of immune system cells: macrophages, T-lymphocytes (T-cells), and B-lymphocytes (B-cells). Macrophages originate in the bone marrow and then migrate to the organs in the lymphatic system. Macrophages recognize and then phagocytize antigens (substances deemed foreign to the body). All but a fragment of the antigen is digested by the macrophage. This remaining fragment protrudes from the cellular surface, where it is then recognized by T- and B-cells, allowing those cells to develop an appropriate immune response.

Both types of lymphocytes (T- and B-cells) originate in the bone marrow. Their differentiation into T- and B-cells depends on where they develop immunocompetence. Immunocompetence is the ability of the immune system to mobilize in response to an antigen; it can be weakened secondary to age-related changes, radiation therapy, chemotherapy, or viral infections. T-cells migrate to the thymus to develop this ability, whereas B-cells develop it before leaving the bone marrow. T-cells travel to lymph nodes, the spleen, and connective tissues, where they wait to phagocytize the antigens in the manner previously described. B-cells function in the same way against free-floating blood-borne pathogens.

There are at least eight types of T-cells with various functions. Two relevant types when considering HIV infection are helper T-cells (CD4) and suppressor T-cells (CD8). The CD4 cells enhance the immune response, whereas CD8 cells regulate the immune response. HIV primarily attacks these two types of T-cells, impairing the body’s immune response. On recognition of an antigen, CD4 cells chemically stimulate production and activation of other lymphocytes to destroy the foreign material. When the action of the T- and B-cells elicits a sufficient immune response, the CD8 cells will halt the action, thus preventing the destruction of normal (uninfected) cells. HIV causes the destruction of the CD4 cells. Declining CD4 cell counts occur in untreated disease; in healthy (uninfected) individuals, CD4 counts should be 500 to 1600 cells/μL. However, because T-cell counts fluctuate somewhat under normal circumstances, the ratio of CD4 to CD8 cells is considered a valuable laboratory value in tracking the progression of the disease (a normal ratio is approximately 2.0, whereas a ratio close to 1.0 is associated with advanced HIV infection).

In the process of identifying and destroying antigens, the normal acquired immune system retains a memory of the antigen. This allows the immune system to respond more rapidly and effectively to the pathogen if it is reintroduced into the body. Herein lies the pertinence of vaccination and the phenomenon of being immune to an illness.

CD4 cell counts

Medical management of HIV infection is most often guided by the CD4 cell count and viral load. For the healthy HIV-negative adult, the average CD4 cell count may fluctuate between 500 and 1600 cells/μL. Typically, ART is initiated soon after an individual learns that they are HIV-positive; ideally, this is before there is a detrimental decline in CD4 cells.

Exercise, stress, seasons of the year, serum cortisol level, and the presence of acute or chronic illness and infection have all been reported to affect CD4 cell counts. ^, The initial CD4 count should be confirmed by repeat testing, and caution should be exercised to avoid overinterpretation of small changes in CD4 test results. The overall trend of CD4 counts is more significant than any single value. In addition to CD4 cell counts, CD4/CD8 ratios are used to evaluate the status of the immune system. In 2012 the Department of Health and Human Services and the WHO began recommending that ART be initiated for HIV-positive individuals, regardless of the CD4 count. In an individual who has not been successfully treated with ART, a CD4 cell count of 200 cells/μL marks a critical point during HIV infection, often indicating that the stage of advanced HIV disease, or AIDS, has been reached. Serious opportunistic infections are likely to occur once this level of immune depletion has been attained in an individual who has not been successfully treated with ART. Table 34.2 is a summary of common ARTs. A complete listing of pharmacological interventions to combat the opportunistic infections associated with HIV infection are beyond the scope of this chapter.

Viral load measurement

Testing for HIV in plasma by measuring viral RNA (copies of HIV per milliliter) has become a standard component of the management of HIV infected patients. In 2013 the WHO began recommending viral load testing as the preferred method for diagnosing and confirming ART treatment failure. There are important prognostic implications for viral load in persons with HIV disease. In patients with higher viral loads, disease progression is more rapid, both immunologically, in terms of the rate of CD4 cell count decline, and clinically, in terms of development of AIDS-defining illness. In addition, the plasma levels in HIV-positive pregnant women directly correlate with the risk of perinatal transmission. Viral load is an important useful marker for judging the effectiveness of various antiretroviral drug interventions. ^, The guidelines established by the WHO recommend routine viral load monitoring at 6 and 12 months, then every 12 months after if the HIV-positive individual is stable on ART. The goal of ART is to have an undetectable viral load in the bloodstream.

The WHO has concerns about the increase in HIV drug resistance, both pretreatment drug resistance and developed resistance to first-line ART. There are several assays available for testing HIV for resistance to antiretroviral agents. Genotype or phenotype testing is used to determine whether the virus has mutated. The results of genotype or phenotype testing provide important information about resistance to specific antiretroviral drugs. If a mutant form is resistant to an antiretroviral drug, the ART regimen may be altered so that the potential for viral suppression is maximized. Changes in the drug combinations used for ART to respond to viral resistance are referred to as salvage therapy. Like genotypic testing, phenotypic testing may not detect small subpopulations of resistant HIV.

Until a functional cure and/or vaccine is discovered, advances will continue to be made in ART. The primary goal of ART is to achieve prolonged suppression of HIV replication. ^, At this time, there are five classes of ART drugs. Entry inhibitors, such as CCR5 antagonists and fusion inhibitors, work to prevent HIV from successfully entering the cell. The CCR5 antagonist currently in use is maraviro (Selzentry); this drug works by blocking the CCR5 coreceptors on an immune cell surface, thereby preventing HIV from entering the cell.

Other classes of drugs work within the cell by interfering with one of three enzymes that are involved with the replication process: reverse transcriptase, integrase, and protease. These classes include nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors (INIs), and protease inhibitors (PIs). In 1987, zidovudine (AZT, brand name: Retrovir), an NRTI, was first approved by the US Food and Drug Administration (FDA). Since that time, several more NRTI drugs have been approved. NNRTIs, such as nevirapine (NVP, brand name: Viramune) and efavirenz (EFV, brand name: Sustiva), also inhibit the reverse transcriptase enzyme, but they are not nucleoside analogs. The NNRTIs bind to the enzymatic binding pocket of the reverse transcriptase gene and block binding by the nucleosides. ^, Like reverse transcriptase, integrase is an enzyme that is active in the early stages of the replication process, and INIs can be used to interrupt its function by preventing the integration of the virus in the host cell’s DNA. INIs include drugs such as dolutegravir (DTG, brand name: Tivicay) or raltegravir (RAL, brand name: Isentress). Another drug target for anti-HIV agents is the protease enzyme, an enzyme necessary for HIV to replicate. The PI drugs are structurally different from other drugs and include agents such as atazanavir (ATV, brand name: Reyataz), darunavir (DRV, brand name: Prezista), and fosamprenavir (FPV, brand name: Lexiva). Pharmacokinetic enhancers, such as cobicistat (Tybost), are used to increase the effectiveness of another drug included in ART.

Triple combination therapy (three different drugs from at least two different classes) has been the mainstay of ART since 1995. ART may be NNRTI or PI based (e.g., NNRTI and PI drugs are used in combination with an NRTI). The current recommendation from the Department of Health and Human Services, for a treatment-naïve patient, is two NRTIs in combination with a third drug (either an INI, an NNRTI, or a PI with a pharmacokinetic enhancer). Because of the rapidly evolving nature of ART drugs, the reader is advised to consult with the CDC and WHO for the most current clinical practice guidelines. There has been a gradual evolution of pharmacology that has allowed for multiple drugs to be combined into one pill. This results in a more manageable ART dosing, which is more convenient and encourages improved patient compliance.

Side effects and toxicities are common with drugs used to treat HIV disease. Purported side effects of NRTIs include peripheral neuropathy, myopathy, anemia, gastrointestinal (GI) disturbances, hepatomegaly, and pancreatitis. NNRTIs may cause rash, liver dysfunction, cognitive problems, and lactic acidosis. PIs may cause lipodystrophy, peripheral neuropathy, GI intolerance, hyperlipidemia, hyperglycemia, and liver toxicity. This list of side effects is cursory, and the full impact of these and other HIV drugs on the various systems of the body is a continually emerging area. Occasionally an individual’s ART regimen is modified to mitigate the side effects that may occur with specific drugs.

Although ART can reduce serum viral loads to undetectable levels, it is not a cure because HIV continues to exist within the lymphoid tissue and the central nervous system (CNS). Another challenge with ART is resistance to one drug in a class of agents, which may induce partial or complete resistance with other agents, depending on the specific mutations involved. ^, In a field that is rapidly changing, specific recommendations for ART are best made by an infectious disease specialist with experience in the management of patients with HIV disease. The major therapeutic decisions include (1) when to initiate therapy, (2) what drugs to prescribe, (3) when to modify therapy, and (4) which drugs to change to. The mortality rate of PLHIV and the incidence of opportunistic infections decreased markedly since 1995 due to triple combination ART becoming available at that time. The role of drugs with immunomodulating activity in combination with ART is also undergoing extensive research. ^, Drug regimens for HIV disease are dynamic, and clinical practice guidelines are consistently updated; many changes in the approach to drug interventions can be expected as HIV infection continues to be a chronic disease. There remains concern regarding the occurrence of noncommunicable diseases among individuals aging with HIV, but few studies have described whether disparities between demographic subgroups are present among individuals on ART with access to care. Racial disparities in the occurrence of diabetes, chronic kidney disease, and hypertension emphasize the need for prevention and treatment options for these HIV populations receiving care in North America.

Vaccines for other antigens

HIV-positive individuals with impaired immune systems respond less well than do uninfected persons to most vaccines for other (non-HIV) antigens. The degree of immunodeficiency present at the time of vaccination has an impact on the response to hepatitis A or B, pneumococcal, and influenza A and B vaccines. Patients with a CD4 count of more than 200 cells/μL have a more successful response to the vaccine. Patients should be informed that the extent and duration of the protective efficacy of these vaccines are still uncertain.

Vaccines and functional cures for human immunodeficiency virus

Vaccination for HIV has the potential to prevent or control disease progression, but a successful vaccine has not yet been found. The development of an effective preventative vaccine for HIV is an area of continuing research. A true cure for HIV would require complete eradication of the virus from body, which might not be feasible. Thus several routes to “functional cures” are currently being studied. This includes exploration of use of therapeutic vaccines, antibody therapy, and gene therapy.

Prevention

Transmission routes of HIV have been well known since the late 1980s. Because the two most common routes of HIV infection are unsafe sex and sharing of needles and/or syringes among IV drug users, the keys to prevention are linked to safer sex practices and, for IV drug users, use of sterile syringes. For decades, use of latex condoms was the mainstay of HIV prevention during sexual activity. More recently, using preexposure prophylaxis (PrEP), in the form of Truvada, has been shown markedly reduce the risk of HIV transmission during sex. ^,

Nutrition

Involuntary loss of more than 10% of baseline body weight in a 12-month period or a 5% loss in baseline body weight in a 6-month period with chronic diarrhea or unexplained weakness and fever constitute HIV wasting syndrome. Early retrospective demographic research in the United States found that 17.8% of individuals with AIDS had wasting syndrome. ^, The ensuing malnutrition contributes to further immunosuppression. With the widespread use of ART, HIV wasting syndrome has declined significantly. Those PLHIV with delayed initiation of ART or poor compliance may still experience weight loss or wasting through the loss of fat mass and lean body mass; this may contribute to muscle fatigue and weakness. Nutritional consultation is critical for those patients experiencing wasting syndrome and as a preventative measure for those who newly diagnosed. Studies have been done investigating the effects of nutritional counseling and other measures such as medications, hormone supplementation, and exercise on lean body mass in patients with HIV wasting syndrome. It has been shown that nutritional counseling, medications to inhibit tumor necrosis factor, androgen supplementation, growth hormone administration, and resistance strength training have all been effective in improving lean body mass. Increased caloric intake alone increases lean body mass but primarily through fat stores. Resistance strength training may prove to be the most beneficial in increasing lean body mass with minimal side effects and minimal cost.

There are new nutritional concerns that have developed since the prolonged use of ART in PLHIV. The development of changes in body fat distribution, dyslipidemia, insulin resistance, lipodystrophy syndrome, sarcopenia, and frailty are currently primary concerns when considering nutritional interventions. Weight loss or reduction in lean body mass may also be a problem for some patients using ART. Comprehensive nutritional intervention is advocated during the early stages of HIV infection to maintain nutritional status. ART compromises nutrition in HIV patients because of complicated drug and nutrient interactions, adverse side effects including diarrhea and nausea, and, in some cases, excessive pill loads that must be consumed. Furthermore, ART has been directly linked to HIV-associated lipodystrophy. This syndrome is marked by various combinations of insulin resistance, hyperlipidemia, visceral adiposity, loss of peripheral fat stores, and dorsocervical fat accrual. Lipodystrophy is a syndrome that makes the nutritional management of HIV more difficult and may necessitate exercise, pharmacological intervention, and diet modifications. Insulin resistance has been observed in approximately 50% of ART users taking a PI, compared with approximately 25% of ART users who are taking an NRTI; this can result in eventual symptomatic atherosclerosis. Dietary modification has only a modest effect on serum lipid concentrations; the use of statins and ART modification may be a more effective treatment.

Diet modification and resistance exercise training have been shown to help reduce total-body and regional fat mass. In addition, the FDA approved a growth hormone–releasing factor to treat visceral fat accumulation in PLHIV diagnosed with HIV lipodystrophy.

Many patients who take antiretroviral drugs also take alternative therapies, including dietary supplements. Some drug-herb-supplement combinations may result in clinically meaningful interactions. Twenty-eight pharmacokinetic studies and case-series/case reports were selected for inclusion in a recent systematic review. Calcium carbonate, ferrous fumarate, some forms of ginkgo, some forms of garlic, some forms of milk thistle, St. John’s wort, vitamin C, zinc sulfate, and multivitamins were all found to significantly decrease the levels of selected antiretrovirals and should be avoided in patients taking these antiretrovirals. Cat’s claw and evening primrose oil were found to significantly increase the levels of antiretrovirals. PLHIV should be monitored for adverse effects while taking these dietary supplements with antiretrovirals. This evidence shows the importance of screening all PLHIV for dietary supplement use to prevent treatment failure or adverse effects related to an interaction.

Integumentary system and neoplasms

Cutaneous disorders develop as many as 90% of all PLHIV. Most HIV-induced skin findings develop only when the CD4 count falls to less than 500 cells/μL. As the CD4 cell count decreases further, multiple cutaneous disorders may develop. Skin conditions may be defined as infectious, neoplastic, or inflammatory; a large percentage of PLHIV will also develop primary pruritus. Chronic itch may be cutaneous, systemic, or psychiatric in nature and can directly impact QOL for PLHIV. Treatment for inflammatory skin conditions may include ART modification, oral antihistamines, topical corticosteroids, topical antipruritic agents, skin moisturizers, psychiatric interventions, or phototherapy.

There are three malignancies common in advanced HIV or AIDS: Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), and cervical cancer. KS was the first neoplastic condition to be related to HIV infection, and it remains the most common in PLHIV who have limited access or poor compliance with ART. The incidence of KS has continued to diminish because of the use of more powerful ART and maintenance of immune status. ^, KS can involve almost every part of the body, but the most common site of initial KS presentations is the skin or mucous membranes. The disorder manifests as cutaneous purple nodular lesions or as rife visceral lesions. AIDS-KS has been intimately associated with the lymphatic system, specifically deficient lymphatic transport, nodal dysfunction, and tumors, which contribute to lymphedema.

In KS there is a broad therapeutic spectrum from cryotherapy to systemic chemotherapy. ART plus chemotherapy is more effective than ART alone in patients diagnosed with severe or progression KS. In NHL, early therapeutic intervention is necessary because of the fast progression of the tumor. A systematic review, conducted in 2015, found that the prevalence of nondiffuse large B-cell lymphoma has declined significantly since the introduction of combination ART, yet the prevalence of Burkitt or Burkitt-like lymphoma has not shown the same reduction; there remains a poor prognosis for those with Burkitt or Burkitt-like lymphoma. The cervical cancer in HIV-positive women seems to be more aggressive than in HIV-negative women and requires early therapeutic intervention. The cancer incidence in patients with HIV is reported to be higher among nonblack patients. The incidence is seven times higher in HIV-positive women, as is the prevalence of a positive HPV viral DNA test, when compared with HIV-negative women.

Several other tumors occur in people with HIV infection: anorectal cancer, lung cancer, malignant testicular tumor, Hodgkin lymphoma, basal cell carcinoma, and malignant melanoma. ^, It is beyond the scope of this chapter to detail all aspects of integumentary and neoplastic concerns; however, the therapist needs to be aware of the importance of differential diagnosis because the skin is the first line of defense of the immune system and further work-up may be warranted. See Table 34.3 for integumentary conditions associated with HIV.

Musculoskeletal system

Musculoskeletal symptoms are common in PLHIV. Knowledge of abnormalities that may occur in the musculoskeletal system is crucial as it influences morbidity and mortality. PLHIV develop inflammatory rheumatic diseases, which require screening, assessment, and management. Arthritis in HIV disease has a wide spectrum of presentations ranging from mild arthralgia to severe joint disability. Arthritides seen in this population has been classified into five groups on the basis of clinical presentation: (1) painful articular syndrome, (2) acute symmetrical polyarthritis, (3) spondyloarthropathic arthritis (Reiter syndrome, psoriatic arthritis), (4) HIV-associated arthritis, and (5) septic arthritis. Standardized diagnostic tests and treatments are the same for PLHIV with musculoskeletal impairments.

Primary abnormalities include osseous and soft tissue infections, polymyositis, myopathy, and arthritis. Spinal infections such as pyogenic discitis, osteomyelitis, spinal tuberculosis, and epidural abscesses can occur with avascular necrosis (AVN) and osteoporosis as common comorbidities of HIV. ^, Secondary musculoskeletal complications are often a result of the various compensatory patterns of gait secondary to HIV-related peripheral neuropathy syndrome or the change in biomechanics of the foot and ankle. These lead to potential spinal changes and back pain. PLHIV should be evaluated from a systems perspective to underscore the primary driver of movement dysfunction.

In PLHIV, acute myopathy manifests as proximal muscle weakness and elevated creatine phosphokinase levels. Patients may have initial symptoms of difficulty with basic activities of daily living (ADLs), such as rising from a chair or climbing stairs. If myopathy is in an acute inflammatory stage, resisted exercise is contraindicated.

AVN, a pathological process that is associated with a variety of medical conditions or pharmacological interventions, has been linked to prolonged use of ART. A systematic review and meta-analysis, published in 2014, found there was a statistically significant increased odds of AVN in PLHIV who were exposed to PI therapy (odds ratio 2.09, 95% confidence interval [CI] 1.01 to 4.31; P = .05). In addition to the higher prevalence of AVN since the widespread use of ART, there is also a notable increase in the incidence of osteoporosis, especially in young men diagnosed with HIV; the higher prevalence of osteoporosis associated with ART becomes further complicated by the increased life-spans and development of frailty as PLHIV progress through the natural course of aging.

Chronic pain is highly prevalent in PLHIV; it has been associated with mental health disorders and is frequently reported with other symptoms. This is discussed in more detail in a later section of the chapter.

Patient reports of musculoskeletal symptoms may indicate possible underlying inflammation, which has been implicated as a key predictor in HIV disease progression, early aging, and non–HIV-related morbidity and mortality. ^, A key difference to consider is the effect of ART medications when side effects of ART may evoke symptoms that may complicate the differential diagnosis. ART drugs may limit pharmaceutical treatment options for musculoskeletal conditions, namely immunosuppressant medications. See Table 34.4 for musculoskeletal conditions associated with HIV. PLHIV continue to have high musculoskeletal symptom burden despite viral suppression and decreased side effect profiles. These symptoms experienced may have underlying pathophysiology due to inflammation, even in the context of viral suppression. Clinicians should proactively ask patients about symptoms that contribute to pain and distress, assist PLHIV with coping mechanisms, and improved QOL.

Cardiopulmonary system

Pulmonary diseases continue to be important causes of illness and death in PLHIV, but changes in therapy and demographics alter their manifestations. The risk for development of specific disorders is related to the degree of immunosuppression, HIV risk group, area of residence, and use of prophylactic therapies. Sinusitis and bronchitis occur frequently in the HIV-positive population, more so than in the general public. The increasing population of HIV-positive drug users is reflected in the increasing incidence of tuberculosis (TB) and bacterial pneumonia.

Anti- Pneumocystis prophylaxis has reduced the incidence of and mortality from Pneumocystis carinii pneumonia (PCP). The PCP-causing organism is usually acquired in childhood, and 65% to 85% of healthy adults possess PCP antibodies. Reactivation of latent infection is responsible for the recurrent fever, dyspnea, and hypoxia that characterize PCP. ^, Adjunctive corticosteroid therapy has improved the outlook for respiratory failure. Multiple studies have shown that the use of corticosteroids in PLHIV in acute respiratory failure did not increase the risk for the development of opportunistic infections.

Mycobacterial infections in PLHIV usually manifest as either Mycobacterium avium complex (MAC) infection or TB. Steadily increasing incidence of infection by Mycobacterium tuberculosis is likely the result of two factors: better medical management of HIV and the development of multidrug-resistant strains of mycobacteria. MAC infection tends to appear late during HIV infection, with the initial infection affecting the GI and pulmonary tracts; this eventually disseminates throughout the body. This disorder is probably not caused by latent reactivation of the organism but rather by primary infection by ingestion or inhalation. Signs and symptoms of MAC infection include pneumonia, fever, weight loss, malaise, sweats, anorexia, abdominal pain, and diarrhea.

As in many other infections, initial signs and symptoms of TB include fever, weight loss, malaise, cough, lymph node tenderness, and night sweats. Pulmonary involvement accounts for 75% to 100% of cases of TB infection in PLHIV, but extrapulmonary infection, especially in lymph nodes and bone marrow, occurs in up to 60% of these individuals as well. ^, Less common areas of infection include the CNS, cardiac, and mucosal tissues. TB is communicable, preventable, and treatable. Tuberculin skin testing with follow-up chest radiographs when appropriate should be available and routinely offered to individuals at HIV testing sites. Individuals at highest risk for concomitant HIV and TB infections include the homeless, intravenous drug users, and prison inmates. ^, The risk of infection in health care personnel and in the public is a concern. Isolation rooms that provide negative-pressure, nonrecirculated ventilation, specific air filters, and higher air exchange rates offer the best protection to health care providers exposed to TB-infected individuals. Properly fitted face masks that filter droplet nuclei should be worn. Monitoring of personnel who work with these populations will identify the need for necessary preventive therapy. The majority of health care facilities require personnel to have yearly screenings and have established guidelines to prevent the spread of TB in their patient population and within their workforce.

Cytomegalovirus (CMV) can affect the GI and respiratory tracts but primarily targets optic structures and the CNS; 40% to 100% of healthy adults possess CMV antibodies. However, an individual who is immunosuppressed becomes more vulnerable to symptoms of infection with CMV. Predominant consequences of HIV-CMV coinfection are unilateral or bilateral deficits in visual acuity, visual field cuts, and blindness. PLHIV are more likely than the general population to have subclinical bursts of CMV replication at mucosal sites. Production of antigens can activate the immune system and stimulate HIV replication, and it could contribute to the pathogenesis of adverse outcomes of aging, such as CVD or neurocognitive impairment.

Since the introduction of ART, the QOL and longevity for PLHIV have significantly improved. However, given the impact and negative effects of the virus and prolonged intervention with ART, the effects of aging from CVDs have emerged as one of the most common causes of death. This accounts for up to 15% of total deaths in high-income countries. As ART availability expands to low-income countries, the burden of CVD mortality will rise. Over the next decade, HIV-CVD disease burden is expected to increase globally. Factors that contribute to the atherosclerotic process and its role in the development of acute coronary syndrome in the setting of infection requires close monitoring in rehabilitation settings.

Clinical CVD tends to appear approximately 10 years before in infected individuals, when compared with the general population. The pathogenesis behind the cardiovascular, HIV-associated complications is complex, involving traditional CVD risk factors, as well as factors associated with the virus itself including chronic inflammation and resultant immune activation, along with metabolic disorders related to ART regimens. Determining the cardiovascular risk among HIV-infected patients, as well as targeting and treating conditions that predispose to CVD, are currently emerging concerns among health care professionals. CVD, especially coronary artery disease, are among the leading causes of death in this population.

Pericardial effusion and myocarditis are among the most commonly reported cardiac abnormalities. Cardiomyopathy, endocarditis, and coronary vasculopathy have also been reported. HIV infection, the medical management of HIV disease, and secondary opportunistic infections can all affect the myocardium, pericardium, endocardium, and blood vessels. ^, Cardiovascular risk in PLHIV depends on several factors: direct and indirect vascular effects of chronic exposure to the virus, metabolic effects from prolonged ART, the normal aging process (important to consider given the increased life expectancy of PLHIV), and other cardiovascular risk factors (such as diet and genetics).

Body fat changes and lipid abnormalities, known as lipodystrophy or fat redistribution syndrome, have been connected to PI use. These body fat changes may have strong implications for patients undergoing rehabilitation interventions. Signs and symptoms of the syndrome vary, and not all need to be present in any patient. However, in both men and women, three main components of the syndrome have emerged. These include changes in body shape, hyperlipidemia, and insulin resistance. Clinically, distinct body shape changes are apparent. The most prevalent include increased abdominal growth, dorsocervical fat pad, benign symmetrical lipomatosis, lipodystrophy, and breast hypertrophy in women. ^, The increased abdominal growth is characterized by a redistribution and accumulation of fat in the central visceral areas of the body. ^, Corresponding symptoms include GI discomfort, bloating, distention, and fullness. In addition to visible signs and symptoms, adverse changes in lipid, glucose, and insulin levels have been reported. Several studies have revealed hyperlipidemia to be present in PLHIV, many of whom, but not all, were undergoing PI therapy.

Prevention of CVD risk remains the first and essential step in a medical intervention. Lifestyle modification, including weight reduction, exercise, smoking cessation, and education on healthy dietary practices, are key target areas. Statins are the primary medication used to treat hypercholesterolemia. They have been shown to slow the progression or promote reduction of coronary plaque and could also exert an antiinflammatory and immunomodulatory effect. Current ARTs are less toxic and more effective than regimens used in the early years. Lipodystrophy and dyslipidemia are the main causes of long-term toxicities. PIs may cause dyslipidemia and lipodystrophy, whereas INIs have a minimal impact on lipids profile and no evidence of lipodystrophy.

Metabolic syndrome, which is a cluster of risk factors for type 2 diabetes and CVD, has become an important public health problem. In HIV, new evidence suggests that the use of optimal waist cut-off points specific for the various ethnic populations is recommended. Although metabolic disorders have been associated indirectly with ART, in the aging HIV population and newer, less metabolically toxic antiretroviral drugs are available. Lipotoxicity and adipokines have been key issues to explain this metabolic syndrome. Prevention strategies and therapeutic options for all metabolic syndrome and CVD need to be addressed in the light of the recent Adult Treatment Panel IV recommendations and the new antiretroviral drugs.

Therapists need to be apprised of various changes in laboratory results and signs and symptoms of metabolic syndrome and cardiac disease when designing an exercise program and facilitating the return to functional activities. Screening guidelines ^, (from the Infectious Diseases Society of America HIV Medicine Association [IDSA HIVMA]) include the following:

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  Monitor fasting lipid levels before beginning highly active antiretroviral therapy (HAART) and during the first 4 to 6 weeks of treatment

  
  
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  Monitor fasting glucose levels before and during HAART

  
  
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  Monitor body weight and body shape changes on a routine basis

See Table 34.5 for effects of HIV treatment on cardiovascular factors and Table 34.6 for cardiovascular risk factors associated with HIV.

Neurological system

The neurological manifestations of HIV disease are numerous and involve the autonomic nervous system (ANS), CNS, and peripheral nervous system (PNS). ^, Over the course of the disease, up to 70% of patients have some form of neurological symptom. Significant progress in understanding and treating the neurologically involved HIV-positive patient has been made over the past decade. However, HIV continues to affect every division of the human nervous system. HIV-positive infants show early, catastrophic encephalopathy, loss of brain growth, motor deficits, and cognitive dysfunction. This static or progressive HIV-encephalopathy is characterized by acquired microcephaly, delay or loss of developmental milestones (motor, mental, and language), and pyramidal tract motor deficits. Unfortunately, neurobehavioral dysfunction in early pediatric AIDS remains unchanged after therapy. Dementia develops in some adult patients despite the use of combination ART drugs, whereas other patients have subtle neurobehavioral changes that diminish the quality of their prolonged lives. HIV infection of the CNS remains an important clinical concern.

A variety of host and viral factors are associated with an increased risk of developing HIV-associated neurocognitive disorders (HANDs). HAND is associated with a decreased survival time and is characterized by an insidious onset and slow progression of cognitive decline. In the early stages, individuals may report reduced concentration, poor memory, and impaired executive functioning. As the condition progresses, the individual’s affect may change, with psychomotor slowing and reduction in motor skills. Approximately 18% to 50% of PLHIV who are on ART have some degree of HAND. ^, As PLHIV are living much longer life-spans, it is critical to differentiate HAND from the more commonly diagnosed dementias. Studies are demonstrating similarities between factors that predispose PLHIV to HANDs and the risk factors of Alzheimer dementia, suggesting the potential for a common pathological mechanism. Evidence has shown that HIV-infected monocytes are carried across the blood-brain barrier and infect the macrophages and microglia in the CNS. ^, HIV enters the CNS early, yet HANDs may not occur until advanced stages of HIV infection. Hypotheses for the development of HANDs in the advanced stages include the loss of immune control with disease progression, heightened immune activation, increased transfer of infected monocytes into the CNS, and variations or mutations in the virus. Because many ART medications have reduced CNS penetration, HANDs continue to pose significant challenges for advanced HIV/AIDS patients. See Table 34.7 for neurological conditions associated with HIV.

TABLE 34.7

Human Immunodeficiency Virus and Neurological Conditions

Condition	Symptoms and Presentation	Prognosis and Treatment
CNS Lymphomas	Cancerous tumors (begin in the brain or result from a cancer that has spread from another site in the body) Almost always associated with the Epstein-Barr virus (EBV) Symptoms: headache, seizures, vision problems, dizziness, speech disturbance, paralysis, and mental deterioration May develop one or more CNS lymphomas	Prognosis is poor owing to advanced and increasing immunodeficiency
Cerebrovascular Accident (CVA): Ischemia or Hemorrhage	Causes include hypertension, blood vessel abnormalities (aneurysms, vein or artery malformations), hypotension, coagulopathies, thrombotic thrombocytopenic purpura, elevated lipids, viral infections of the heart muscle, herpes zoster, hepatitis C, and cocaine or heroin use Characterized by the abrupt onset of weakness, language problems, or sensory loss Symptoms often occur on only one side of the body Imaging studies help to differentiate stroke, hemorrhage, infection, and tumors	Treatment parallels the HIV-negative population CVA diagnosed <3 h after onset may be a candidate for tissue plasminogen activator (tPA); tPA is contraindicated in cases of brain hemorrhage Lipid-lowering drugs (statins), blood thinners such as warfarin (Coumadin), or antiplatelet agents such as aspirin or clopidogrel (Plavix) are indicated Specific causes of stroke may require other forms of treatment Brain hemorrhages may require surgery Prognosis depends on size and location; recovery is greatest during the initial few weeks, but improvement often continues for months Inpatient and outpatient rehabilitation is often helpful Preventive treatment parallels the HIV-negative population; includes antiplatelet agents or blood-thinning drugs, removal of plaque from the walls of carotid arteries, and newer techniques of endovascular stenting
Cryptococcal Meningitis	Manifests as meningitis, a space-occupying lesion, or meningoencephalitis The fungus first invades the lungs and spreads to the covering of the brain and spinal cord, causing the inflammation Symptoms: fatigue, fever, headache, nausea, memory loss, confusion, photophobia, stiff neck, altered vision, drowsiness, and vomiting Develops when CD4 cell counts fall to less than 100 cells/μL	If untreated, may lapse into a coma and die Treatment relies on amphotericin B (Fungizone), which may be combined with flucytosine (Ancobon) Alternative for less severe cases is fluconazole (Diflucan), which is also the drug of choice for long-term prophylaxis (preventive therapy) Amphotericin B is an alternative maintenance therapy for those who relapse on fluconazole or do not tolerate it Hydrocephalus can occur; requires a ventriculoperitoneal shunt Visual loss can be addressed by optic nerve surgery
Cytomegalovirus (CMV) Infections	Herpesvirus that causes infection of the brain, spinal cord, meninges, or nerve roots Lead to neurological problems such as encephalitis, myelitis, retinitis, polyradiculitis, peripheral neuropathy, or mononeuritis multiplex Infection of the spinal cord and nerves can result in weakness in the lower limbs and paralysis, severe lower back pain, and loss of bladder function Findings include low-to-normal glucose, normal-to-high protein, and increased numbers of white blood cells	Untreated CMV encephalitis is almost always fatal and causes death within days to weeks Anti-CMV drugs must be started immediately, often based on a suspected rather than proven diagnosis Treatment relies on ganciclovir (Cytovene) and foscarnet (Foscavir), used alone or in combination when monotherapy fails Lifelong maintenance treatment is often necessary
Distal Sensory Polyneuropathy	Damage to sensory nerves in the extremities Most common type of HIV-associated neuropathy Nerves may be injured directly by HIV or by HIV-induced macrophages that secrete neurotoxic substances May also be caused by nutritional and vitamin imbalances or drug toxicity (especially use of d4T [stavudine, Zerit], ddI [didanosine, Videx], or ddC [zalcitabine, Hivid]) Occurs at any stage of HIV disease	Treatment of symptoms may include local ointments (capsaicin, Aspercreme), antidepressant medications (amitriptyline [Elavil]), or antiepileptic medications (gabapentin [Neurontin], lamotrigine [Lamictal], carbamazepine [Tegretol]) Duloxetine (Cymbalta; an SSRI antidepressant) is FDA approved for painful diabetic polyneuropathy Pregabalin (Lyrica; antiepileptic drug) Drugs should be chosen that are unlikely to interact with or influence the effectiveness of ART Lidoderm patches may provide partial pain relief without any systemic side effects and can be combined with oral drugs.
Herpesvirus Infections	Herpes zoster virus can infect the brain and produce encephalitis or myelitis Signs of shingles include painful blisters, itching, tingling, and nerve pain	Anti-herpes drugs: standard treatment for shingles is acyclovir; other medications include famciclovir and valacyclovir Nerve blocks: anesthetic drugs and/or steroids injected into peripheral nerves or into the spinal column Drugs normally used to treat depression, epilepsy, or severe pain are sometimes used for the pain of shingles; nortriptyline (antidepressant) is frequently used for shingles pain; pregabalin is an epilepsy medicine used for pain after shingles Skin treatments: creams, gels, and sprays may provide temporary relief from pain; capsaicin has shown good preliminary results; the patch form of the anesthetic lidocaine provides pain relief for some people with shingles
HIV-dementia Complex (HIV-associated Encephalopathy)	Occurs primarily in persons with advanced HIV infection Mild cognitive impairment may occur in earlier stages Symptoms: encephalitis, behavioral changes, and a gradual decline in cognitive function (decreased concentration, memory, and attention) May develop severe global dementia with memory loss and language impairment Progressive slowing of motor function (decreased balance, weakness, decreased coordination) and loss of dexterity and coordination	Can be fatal if left untreated If HIV-dementia develops during treatment with ART, additional or alternative agents should be tried Neuroprotective therapies or global memory-enhancing agents such as memantine (Namenda) or donepezil (Aricept) may be useful Polypharmacy can affect thinking and memory and make symptoms worse
Inflammatory Demyelinating Polyneuropathy (IDP)	Inflammation of the myelin sheath that surrounds the spinal and peripheral nerves Acute form of IDP (AIDP), also known as Guillain-Barré syndrome (GBS) Characterized by rapid onset and progression over hours to weeks Chronic form (CIDP) has slower onset and progression over weeks to months, sometimes with a relapsing course Both forms are autoimmune conditions in which the immune system attacks nerves Causes varying degrees of weakness and sensory loss, which can develop in the limbs Nerves around the head may be affected and cause symptoms of facial weakness and double vision. Other symptoms may include pain and diminished reflex responses May have difficulty with urination and bowel movements, respiratory paralysis, irregular heartbeat, and dangerously high or low blood pressure	Treatment and response rates are similar to the HIV-negative population Intravenous immunoglobulin (IVIG), a highly concentrated antibody infusion from many pooled blood donations, is the primary treatment Plasmapheresis (removal of antibodies from the blood) may be helpful CIDP may also necessitate use of corticosteroids such as prednisone
Meningitis	Inflammation of the meninges, the membranes surrounding the brain and spinal cord Signs and symptoms are malaise, fever, stiff neck, photophobia, and headache; less common are cranial neuropathies (one-sided facial weakness or double vision), confusion, drowsiness, and personality changes HIV invades the brain early and may cause meningitis within days to weeks after infection Chronic meningitis, or episodes of idiopathic acute (rapid onset) meningitis can occur anytime during the course of HIV disease	Treatment and prognosis vary by the specific cause of meningitis, severity at presentation, delay from symptom onset to treatment, and status of immunosuppression
Mononeuritis Multiplex	Painful condition involving isolated nerves over the arms, legs, or trunk Nerves are affected asymmetrically Involvement of >2 nerves is generally seen in advanced HIV Burning or shooting pain down an arm or leg, then (even if resolving) another burning pain emerges over another nerve pathway in a different arm or leg Weakness in the distribution of specific nerves is common Nerves can be affected in the head and the body	Occurring early in HIV infection May resolve with ART IVIG or plasmapheresis should be considered in early or late HIV stages Advanced HIV disease may require anti-CMV medications (ganciclovir, foscarnet)
Myopathy	May be due to drug toxicity (statins, ddI, or AZT), bacterial, viral, or other infections Polymyositis is caused by an abnormal immune response HIV wasting syndrome may result from HIV infection itself. Progressive muscle weakness is the typical presentation; the speed of progression depends on the cause	If due to drug toxicity, discontinue or replaced medication Muscle infections treated with drugs specific to the responsible bacterium, virus, or other infectious agent Inflammation from an overactive immune system can be treated with corticosteroids
Neurosyphilis	Sexually transmitted infection caused by the spiral-shaped Treponema pallidum bacterium T. pallidum gains access to the body through tiny abrasions of the skin or mucous membranes; this organism may invade the CNS a few months after initial infection May proceed rapidly from the primary stage (skin chancres, or lesions, appearing about 21 days after infection) to secondary syphilis (skin rash) and tertiary syphilis (infection of different organs, including the brain) as early as 2 months after exposure Tertiary syphilis may cause hearing loss, dizziness or vertigo, headache, failing vision, cognitive impairment, personality changes, peripheral polyneuropathy, gait imbalance, seizures, or CVA	Antibiotic use depends on the stage of syphilis and follows general guidelines Most common are different forms of penicillin Although HIV-infected patients with neurosyphilis respond to antibiotics, they are less likely to have serological improvement (compared with HIV-negative individuals) HIV-associated neurosyphilis may be more difficult to treat and more aggressive
Polyradiculopathy	Damage to the nerve roots where the nerves exit the spinal cord to form peripheral nerves May be caused by CMV, or lymphoma (less likely); may be idiopathic Rapidly progressive ascending numbness, pain, and weakness affecting the legs, and later occasionally the arms, is characteristic of the CMV form Early bowel and bladder control problems may suggest the syndrome More benign, slower clinical progression characterizes the idiopathic form	CMV polyradiculopathy is rapidly fatal without therapy Treatment with foscarnet or ganciclovir may improve or stabilize the condition ART may be useful Idiopathic form may improve spontaneously, without treatment
Primary Central Nervous System Lymphoma	Characterized by the growth of abnormal lymphocytes, or white blood cells (B- and T-cells) Occurs in the brain, rarely in the spinal cord; causes brain lesions and changes in mental functioning In almost all cases, EBV is found in the lymphoma-related lesions or the CSF Often associated with CD4 cell counts less than 100 cells/μL Symptoms: impaired cognition, aphasia, hemiparesis, and seizures Onset is often subtle and progression slower	Prognosis is generally poor Whole brain radiation therapy (radiotherapy) has been the mainstay of treatment; provides for a median survival of 2–5 months Steroids are required for at least 48 h before radiotherapy to minimize swelling; steroids should be continued throughout the course of treatment High-dose methotrexate has been used with some success, given as frequently as every week for five cycles; combining methotrexate and radiotherapy can achieve survival of 1–2 years Experimental chemotherapy agents include thiotepa (Thioplex) and procarbazine (Matulane) ART should be continued
Progressive Multifocal Leukoencephalopathy (PML)	Characterized by widespread demyelinating lesions (around nerves in the brain and spinal cord) and caused by the JC papovavirus Symptoms: mental deterioration, vision loss, speech disturbances, ataxia, paralysis, brain lesions, and coma Some may have compromised memory and cognition Seizures may occur when CD4 cell counts fall below 200 cells/μL Onset is usually weeks to months	Relentlessly progressive; death usually occurs within 6 months of initial symptoms Typically progresses to severe dementia and death over several months Whether ART improves survival remains controversial Survival correlates with suppression of plasma HIV viral load and higher CD4+ cell counts Death may result not from PML, but from end-stage immunodeficiency Some positive response has been reported with use of cidofovir (Vistide)
Psychological and Neuropsychiatric Disorders	Occurs in different phases of the HIV infection; may take on various and complex forms Some illnesses are caused directly by HIV infection of the brain, whereas other conditions may be triggered by the drugs used to combat the infection Symptoms include anxiety disorder, depressive disorders, increased thoughts of suicide, paranoia, dementia, delirium, cognitive impairment, confusion, hallucinations, behavioral abnormalities, malaise, and acute mania	Treatment options include antidepressants and anticonvulsants Psychostimulants may also improve depressive symptoms and combat lethargy Antidementia drugs may relieve confusion and slow mental decline Benzodiazepines may be prescribed to treat anxiety Psychotherapy may help
Toxoplasmosis	Caused by the parasite Toxoplasma gondii Symptoms include encephalitis, fever, severe headache that does not respond to treatment, weakness on one side of the body, seizures, lethargy, increased confusion, vision problems, dizziness, problems with speaking and walking, vomiting, and personality changes Onset is over days to weeks	Condition is treatable, most improve by day 14 of therapy Generally responsive to intravenous antibiotics, and response to therapy is often rapid Agents of choice are sulfadiazine combined with pyrimethamine and folinic acid; for people with sulfa intolerance, clindamycin is an alternative Steroids may be used to reduce associated swelling in the brain After the initial regimen is completed, oral maintenance treatment, usually TMP-SMX (Bactrim, Septra), is continued indefinitely to suppress reactivation of the parasite Prognosis is linked to parallel treatment with ART to raise CD4 cell count
Tuberculosis Meningitis	Bacterial disease caused by Mycobacterium tuberculosis (can be suspended in tiny droplets in the air and transmitted person to person by inhalation) May cause persistent headache, fever, confusion, hemiparesis, seizures, stiff neck, double vision, or hearing loss Hydrocephalus associated with tuberculosis may lead to drowsiness or stupor and, later, coma Spinal cord damage can occur if the vertebrae are infiltrated by TB (Pott disease) or from abscesses inside or outside the spinal cord	Triple antibiotic therapy: isoniazid, rifampin (Rifadin), and pyrazinamide, for 12–24 months is required In cases of drug-resistant TB, a fourth drug, ethionamide (Trecator), should be administered ART should be continued Significant interactions can occur between rifampin and PIs, so an alternative anti-TB drug may be necessary
Vacuolar Myelopathy	Causes the protective myelin sheath to pull away from nerve cells of the spinal cord, forming small holes called vacuoles in nerve fibers Symptoms include weak and stiff legs and unsteadiness when walking; walking becomes more difficult as the disease progresses, may necessitate use of a wheelchair	Prognosis is poor, options are limited, and care is primarily supportive May improve after starting ART to stabilize spinal cord damage; maximally potent ART is required l-Methionine (also known as SAMe, a common dietary supplement) is an experimental treatment

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