Identification of the clinical problem

Initially recognized in 1982, acquired immunodeficiency syndrome (AIDS) has been one of the leading causes of death among young adults in the United States since that time. Even with significant advancements in the medical management of the disease, there continues to be a devastating impact in the developing world.^1,2 The course of human immunodeficiency virus (HIV) disease in industrialized nations, including the United States, has changed dramatically as a result of advancements in medications used to treat the disease, as well as increased public awareness and the expansion of programs in poverty-stricken areas. Although the disease was once considered a death sentence, the long-term prognosis for those diagnosed with HIV/AIDS has drastically changed in most industrialized countries. In the United States, HIV is no longer found in the top 10 causes of death for the entire adult population. Yet, HIV is the seventh leading cause of death in young adults (age 20 to 24 years); for both older teens (ages 15 to 19 years) and young teens (ages 10 to 14 years), HIV is ranked fourteenth; for children (ages 5 to 9 years), HIV drops to nineteenth on the list.³ Although still alarming, this is actually an improvement compared with the 1990s. Most epidemiologists and clinicians attribute improved life expectancy to the impact of new, highly active antiretroviral therapies (HAART). Implementation of these medications has resulted in a decline in AIDS deaths nationally.^4,5 However, the incidence of HIV disease, which demonstrated some decrease in the 1990s, demonstrated an increase from 1999 to 2006. HAART regimens have fostered longevity for many, resulting in the evolution of HIV infection into a chronic disease. Individuals previously disabled by the disease now have the potential to return to work and functional activities and often can expect to live a normal life expectancy. Despite these gains, HIV disease, related comorbidities, and the side effects of medications used to treat the disease have a great impact on rehabilitative medicine because of the multisystem involvement, which often progresses slowly throughout the life span. The advancements in medications that have led to increased life expectancies and improved functional capabilities have also led to a greater demand for rehabilitative services.

HAART has slowed and prevented the progression from HIV infection to AIDS and from AIDS to death.⁶ In communities with access to antiretroviral medications, the incidence of perinatally acquired AIDS has declined significantly as a result of administration of HAART during pregnancy.⁷ Unfortunately, perinatal transmission of the virus in developing nations continues to be a crisis.

The clinical and pathological information about this disease is constantly increasing. Certainly, our understanding of the disease process and advances in drug regimens will change between the writing and the publication of this book. Changes in terminology reflect this evolution of clinical knowledge. The definitions used throughout this chapter reflect current usage.

The virus thought to be responsible for the transmission of AIDS was first identified in 1984; it was named human immunodeficiency virus in 1986 at the International Conference on AIDS in Paris. A second virus, HIV-2, was soon after identified in western Africa, and the original strain was renamed HIV-1. Infection caused by HIV-2, less widely distributed, has since been established in Europe and in South, Central, and North America. Both HIV-1 and HIV-2 have resulted in AIDS, but evidence suggests that HIV-2 may be less virulent than HIV-1. In addition to these subtypes, several strains or mutated forms of HIV-1 have been identified. Different strains reflect variations in cellular affinities and resistance to medications. The context of discussion for the purpose of this chapter will be HIV-1, herein discussed as HIV. HIV infection is identified via a positive HIV antibody screening test (enzyme immunoassay [EIA]) and confirmation with a supplemental HIV antibody test (Western Blot) or a positive result from an HIV virological test (nucleic acid detection test, p24 antigen test, or viral culture).

In 2008 the Centers for Disease Control and Prevention (CDC) revised its definition of AIDS and its classification system of HIV disease. To reflect current scientific knowledge, the new system elucidates the importance of CD4⁺ T-lymphocyte cell counts as indicators for pharmacological disease management. Based on laboratory criteria and clinical presentation, the disease is classified into four stages. Stage 1 has no AIDS-defining condition and either a CD4⁺ T-lymphocyte count greater than or equal to 500 cells/mcL or a ratio of CD4⁺ T-lymphocytes to total lymphocytes greater than or equal to 29%. Stage 2 also has no AIDS-defining condition and either a CD4⁺ T-lymphocyte count of 200 to 499 cells/mcL or a ratio of CD4⁺ T-lymphocytes to total lymphocytes of 14% to 28%. Stage 3 is classified by the CDC as AIDS; it is defined as a CD4⁺ T-lymphocyte count less than 200 cells/mcL or a ratio of CD4⁺ T-lymphocytes to total lymphocytes less than 14% or documentation of an AIDS-defining condition (Box 31-1). A fourth stage was also identified as HIV Infection, Stage Unknown (for cases in which no information is obtained regarding the CD4⁺ T-lymphocyte counts or ratios or regarding any AIDS-defining conditions); the primary use of this stage is for surveillance purposes.⁸ The entire spectrum of illness from initial diagnosis to AIDS can be covered by the term HIV disease. In addition, the terms acute HIV infection, asymptomatic HIV disease, symptomatic HIV disease, and advanced HIV disease (AIDS) are used throughout this chapter. In general, asymptomatic HIV disease corresponds with Stage 1, symptomatic HIV disease with Stage 2, and advanced HIV disease (AIDS) with Stage 3. Table 31-1 presents the various modifiers of quality of life throughout the various stages of HIV disease.

Stage 2: Symptomatic Disease, HIV infection 201-499 cells/mcL Emergence of symptoms such as thrush, night sweats, low-grade fevers, oral hairy leukoplakia, peripheral neuropathy; commonly taking antiretroviral drugs and/or Pneumocystis jiroveci prophylaxis Stage 3: AIDS Disease <200 cells/mcL Opportunistic infections such as extensive candidiasis, cryptococcal meningitis; Kaposi sarcoma; tuberculosis; P. jiroveci pneumonia; lymphomas; commonly taking antiretroviral drugs, chemotherapy, antibiotics, and so on

Epidemiology

It is currently estimated that over 30 million people are infected with HIV globally. In the United States, the CDC estimated that 1.1 million adults and adolescents were HIV positive at the end of 2006. Because of complex social and economic factors, African Americans are disproportionally affected, with approximately half of the cases in the United States involving this minority group. Alarmingly, it is estimated that approximately 25% of individuals in the United States infected with HIV are unaware of the infection.⁹

In the most recent publication of the World Health Report from the World Health Organization (WHO), HIV/AIDS is the sixth leading cause of death worldwide, with an estimated 2.04 million deaths per year.¹⁰ Worldwide, of the 33 million people (all ages) living with HIV, 30.8 million are adults, 15.5 million are women, and 2.0 million are children (under the age of 15 years). New HIV infections in 2007 totaled 2.7 million, with 2.3 million in adults and 370,000 in children under 15 years old. Global AIDS deaths totaled nearly 2.0 million; adult deaths were 1.8 million, whereas children under age 15 years totaled 270,000.¹¹ It was estimated that in 2006 the United States had approximately 14,561 deaths from AIDS-related illnesses.⁹

Tuberculosis (TB) is a former leading microbial killer; it is caused by infectious bacteria that spread through the air in microscopic droplets. WHO estimates that there were 9.27 million new TB cases in 2007; of those, 1.37 million cases (14.8%) were in HIV-positive individuals. Approximately 456,000 deaths caused by TB occurred in HIV-infected individuals (23% of the estimated 2 million HIV deaths were caused by TB).¹²

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 (Figure 31-1). The first is the innate, or inborn, component, which includes the skin, the cilia and mucosal linings of the respiratory and digestive systems, the gastric fluids and enzymes of the stomach, and the phagocyte cells. 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, starts in utero, and continues throughout life. It is acquired (or antibody) immunity that is most pertinent to understanding HIV infection and its progression.

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 AIDS.^13,14

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.¹⁵

Both of the 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. 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.¹⁵

There are at least eight types of T cells with various functions. Two relevant types are helper T cells (CD4) and suppressor T cells (CD8). The helper T cells enhance the immune response, whereas suppressor T 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 is a sufficient immune response, the CD8 cells will halt the action, thus preventing the destruction of normal (uninfected) cells. The HIV virus 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/mcL. 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.

In the process of identifying and destroying antigens, the 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.¹⁵

Pathogenesis of HIV disease

HIV belongs to a class of viruses known as retroviruses, which carry their genetic material in the form of ribonucleic acid (RNA) rather than deoxyribonucleic acid (DNA). HIV primarily infects the mononuclear cells, especially CD4 and macrophages, but B cells are also infected.¹⁶ HIV binds to the receptor sites on the surface of the CD4 lymphocytes, eventually fusing with and then entering the cells. Reverse transcriptase released from the HIV allows a DNA copy of the virus to be made within the host cell, which then becomes integrated into the host cell genome. Other enzymes, such as integrase and protease, turn the lymphocyte into a “virus factory,” and replicated virions bud out of the cell to infect others.

Within days of acute HIV infection, lymph nodes become sites of rampant viral replication, and viral loads in the blood are high. During the stage of acute HIV infection, the individual may remain asymptomatic or may experience nonspecific and self-limited flulike symptoms—fever, diarrhea, myalgias, and fatigue—for a period of 2 to 12 weeks. In the weeks after an acute infection, the body gradually produces an antibody response. The point at which antibodies can be detected with a blood test is known as seroconversion. Typically, seroconversion occurs within 3 months of the time of infection, but it can take as long as 12 months. Thus there is a period of time after HIV infection when the result of an HIV antibody test (the most commonly used test to determine HIV status) will be negative.

In asymptomatic HIV disease or Stage 1, individuals will have a positive antibody test result. This stage may last from 1 to 20 years. Although generally asymptomatic, individuals in this stage may express periods of generalized lymphadenopathy. Laboratory tests may reveal slowly declining immune dysfunction, as evidenced by an abnormally low CD4 cell count and an abnormal CD4/CD8 ratio. The viral load is typically at a “set point” during most of the asymptomatic stage of HIV disease. This set point is typically much lower than the viral load occurring during the period of acute infection. The viral load will inevitably escalate as the disease progresses.

As CD4 cell counts decline and viral load escalates, the individual will eventually enter Stage 2, or symptomatic HIV disease. With the continuing advancements in medications, this stage may last several years. Improved effectiveness of medications, increasing access to health care services, and medical comorbidities all have a large influence on the length of time a patient is considered to be in Stage 2. CD4 cell counts are declining and viral loads are increasing. Concurrently with these laboratory value abnormalities, the individual begins to have one or more of an array of symptoms such as weight loss, fatigue, night sweats, fever, thrush, yeast infections, prolonged recovery from other illnesses, or neurological complications.

When the CD4 cell count drops below 200 cells/mcL, the individual is diagnosed with an opportunistic infection or other AIDS-defining illness, or the individual demonstrates wasting syndrome or HIV-related dementia, he or she is reclassified as being in Stage 3—advanced HIV disease or AIDS. It is possible for patients in this stage to demonstrate remarkable recovery in terms of both laboratory values and function with HAART. Individuals who do not have access to HAART, or individuals in whom HAART has failed, will eventually die as a result of the effects of opportunistic infections that inevitably occur. Quality-of-life issues throughout the stages of HIV disease are described in Table 31-1.

Medical management

Cell counts and prophylaxis

Pharmacological interventions to combat the opportunistic infections associated with HIV infection are beyond the scope of this chapter, but a simplified summary of clinical information is pertinent. 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 is approximately 1000 cells/mcL. However, counts fluctuate over time and may range from 500 to 1600 cells/mcL.¹⁷ A CD4 cell count of 200 cells/mcL marks a critical point in the course of HIV infection, often indicating that the stage of advanced HIV infection or AIDS has been reached. Serious opportunistic infections are likely to occur once this level of immune depletion has been attained.^18–20

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. Thus the initial CD4 lymphocyte numbers should be confirmed by repeat testing. Caution should be exercised to avoid overinterpreting small changes in CD4 lymphocyte test results. The overall trend of CD4 counts is more important than any single value. Testing is typically done at a frequency of four times annually. In addition to CD4 cell counts, CD4/CD8 ratios are used to evaluate the status of the immune system. CD4 counts above 500 cells/mcL indicate no need for antiretroviral therapy because individuals are generally asymptomatic. It is currently recommended that HAART be initiated when CD4 levels are below 350 cells/mcL, with individual parameters influencing the decision.²¹ CD4 cell counts below 200 cells/mcL are an indication for prophylactic Pneumocystis jirovechi (previously referred to in the literature as Pneumocystis carinii; this text will refer to the current terminology) pneumonia (PCP) and toxoplasmosis measures. Persons with counts below 100 cells/mcL may also receive prophylactic agents against cytomegalovirus (CMV) infection, infection with Mycobacterium avium complex (MAC), and fungal infections such as cryptococcosis and candidiasis.¹³ In addition, it is recommended that HIV-positive pregnant women, those with HIV-associated nephropathy, and those co-infected with the hepatitis B virus be started on a HAART regimen immediately.²² Table 31-2 is a summary of common pharmacological agents prescribed to combat opportunistic infections and, most pertinent to rehabilitation, their potential side effects.

TABLE 31-2 

HIV DRUGS BY CLASS

Brand NAME	Generic NAME	DOSE	SIDE EFFECTS	FDA APPROVAL	COMMENTS
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)
Combivir	Zidovudine and lamivudine	One tablet twice a day Contains two NRTIs in one tablet

Similar side effects to Retrovir (zidovudine) and Epivir (lamivudine). Please note Retrovir’s and Epivir’s Black Box warnings. September 27, 2007 Take with or without food. Emtriva Emtricitabine One 200-mg capsule once a day Black Box warning: Buildup of acid in the blood; fatty liver; should be used carefully by people with hepatitis B. Otherwise, minimal side effects. July 2, 2003 Take with or without food. Epivir Lamivudine One 300-mg tablet once a day or one 150-mg tablet twice a day Black Box warning: Buildup of acid in the blood; fatty liver; should be used carefully by people with hepatitis B. Otherwise, minimal side effects. November 17, 1995 Take with or without food. Approved for treatment of hepatitis B virus infection at a lower dose. Individuals with both viruses should use the higher dose. Epzicom (Kivexa in some countries) Abacavir and lamivudine Similar side effects to Epivir (lamivudine) and Ziagen (abacavir). Please note Epivir’s and Ziagen’s Black Box warnings. August 2, 2004 Take with or without food. Need to be tested for the HLA-B*5701 gene to reduce the risk of a severe allergic reaction. Retrovir Zidovudine One 300-mg tablet twice a day March 19, 1987 Take with food to minimize stomach discomfort. Do not take with Zerit. Trizivir Abacavir, zidovudine, and lamivudine Similar side effects to Retrovir (zidovudine), Epivir (lamivudine), and Ziagen (abacavir). Please note Retrovir’s, Epivir’s, and Ziagen’s Black Box warnings. November 14, 2000 Take with or without food. Need to be tested for the HLA-B*5701 gene to reduce the risk of a severe allergic reaction. Truvada Tenofovir and emtricitabine Similar side effects to Viread (tenofovir) and Emtriva (emtricitabine). Please note Viread’s and Emtriva’s Black Box warnings. August 2, 2004 Take with or without food. Videx EC (generic is now available in the United States) Didanosine One 400-mg capsule once a day or one 250-mg capsule once a day if <132 lb October 31, 2000 Take on an empty stomach. Can be taken at the same time as other HIV medications except for the protease inhibitors (PIs) Aptivus, Prezista, and Reyataz. Avoid alcohol. Viread Tenofovir One 300-mg tablet once a day October 26, 2001 Take with or without food. Approved for treatment of the hepatitis B virus. Can raise Videx EC level in the blood and increase side effects. Zerit Stavudine One 40-mg capsule twice a day or one 30-mg capsule if <132 lb June 24, 1994 Take with or without food. Do not take with Retrovir or Combivir. Ziagen Abacavir One or two 300-mg tablets once a day Black Box warning: Severe allergic reactions (symptoms include fever; rash; severe nausea, diarrhea, abdominal pain; sore throat; cough; and shortness of breath); buildup of acid in the blood; fatty liver. December 17, 1998 Take with or without food. Need to be tested for the HLA-B*5701 gene to reduce the risk of a severe allergic reaction. NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs) Rescriptor Delavirdine Two 200-mg tablets twice a day Rash, increased liver enzymes, and headaches. April 4, 1997 Take with or without food. May need to reduce the dose of any PIs being taken at the same time. Sustiva (also known as Stocrin) Efavirenz One 600-mg tablet once a day. Rash; central nervous system symptoms, such as drowsiness, insomnia, confusion, inability to concentrate, dizziness, and vivid dreams; increased liver enzymes; false-positive drug testing (marijuana); and birth defects if taken during pregnancy. September 17, 1998 Take on an empty stomach at bedtime to reduce side effects. The dosage of some PIs may need to be increased or boosted with Norvir. Intelence Etravirine Two 100-mg tablets twice a day. Rash, nausea. June 18, 2008 Take with food. May not be combined with certain Norvir boosted PIs, but other PIs must be boosted with Norvir; Do not use with other NNRTIs. Viramune Nevirapine One 200-mg tablet once a day for 14 days, then one 200-mg tablet twice a day. Black Box warning: Severe, life-threatening liver problems, notably among women with T-cell counts >250; severe skin reactions; careful dosing and monitoring needed at start of treatment. June 21, 1996 Take with or without food. Dosage of certain PIs may need to be increased or boosted with Norvir. Do not use with Reyataz. Atripla Efavirenz, tenofovir, and emtricitabine One tablet once a day. Contains two nucleoside reverse transcriptase inhibitors (NRTIs) and one NNRTI in one tablet. Similar side effects to Sustiva (efavirenz), Viread (tenofovir), and Emtriva (emtricitabine). Please note Viread’s and Emtriva’s Black Box warnings. August 2, 2004 Can be used with or without other HIV medications. Take on an empty stomach at bedtime to reduce side effects. PROTEASE INHIBITORS (PIs) Aptivus Tipranavir Two 250-mg capsules plus two 100-mg Norvir capsules twice a day. June 22, 2005 Take with food. Approved only for treatment-experienced patients. Do not take with other PIs except for Norvir. Crixivan Indinavir Two 400-mg capsules twice a day; preferred regimen is two 400-mg capsules twice a day plus one or two 100-mg Norvir capsules twice a day. Kidney stones, nausea, vomiting, diarrhea, increased cholesterol, increased triglycerides, increased glucose (sugar), lipodystrophy, increased bilirubin (not harmful), increased bleeding in patients with hemophilia. Others: headache, weakness, blurred vision, dizziness, rash, metallic taste, low platelets, hair loss, anemia. March 13, 1996 Take on an empty stomach or with a light, low-fat snack. If taking the preferred dose, take with or without food. Drink six glasses of water each day to prevent kidney stones. Invirase Saquinavir Two 500-mg capsules plus one 100-mg Norvir capsule twice a day. Nausea, diarrhea, stomach discomfort, headache, increased cholesterol, increased triglycerides, lipodystrophy, increased glucose (sugar), increased liver enzyme levels, and increased bleeding in patients with hemophilia. December 6, 1995 Must be used with Norvir. Take with food. Kaletra (also known as Aluvia) Lopinavir and ritonavir Two tablets twice a day or four tablets once a day. Contains two PIs in one tablet. Nausea, diarrhea, stomach discomfort, headache, increased cholesterol, increased triglycerides, lipodystrophy, increased glucose (sugar), increased liver enzyme levels, and increased bleeding in patients with hemophilia. September 15, 2000 Take with or without food. Must be taken twice a day and dose may need to be increased if taken with certain other medications. Lexiva (also known as Telzir) Fosamprenavir Two 700-mg tablets twice a day or two 700-mg tablets plus one 100-mg Norvir capsule once or twice a day. Skin rash, nausea, diarrhea, stomach discomfort, headache, increased cholesterol, increased triglycerides, lipodystrophy, increased glucose (sugar), increased liver enzyme levels, and increased bleeding in patients with hemophilia. October 20, 2003 Take with or without food. If other PIs have been taken in the past, only take the twice-a-day, Norvir boosted combination. Norvir Ritonavir Six 100-mg capsules twice a day. Nausea, vomiting, diarrhea, appetite loss, numbness or tingling around the mouth, increased cholesterol, increased triglycerides, lipodystrophy, and diabetes. March 1, 1996 The full dose is rarely used. It is most often used to boost the levels of other PIs in the blood. Needs refrigeration in hot weather. Prezista Darunavir Two 400-mg tablets plus one 100-mg Norvir capsule once a day (for those starting HIV medication) or one 600-mg tablet plus one 100-mg Norvir capsule twice a day. Nausea, diarrhea, stomach discomfort, headache, increased cholesterol levels, increased triglycerides, lipodystrophy, increased glucose (sugar), increased liver enzyme levels, inflammation of the nose and throat, and increased bleeding in patients with hemophilia. June 23, 2006 Take with food. Must be used with Norvir. Reyataz Atazanavir Two 200-mg capsules once a day or one 300-mg capsule plus one 100-mg Norvir capsule once a day. Increased bilirubin (not harmful), abnormal electrocardiogram results, increased glucose (sugar), lipodystrophy, and increased bleeding in patients with hemophilia. June 20, 2003 Take with food. Do not combine with Viramune. Regimen may vary depending on other medications being taken. Viracept Nelfinavir Two 625-mg tablets twice a day or five 250-mg tablets twice a day or three 250-mg tablets three times a day. Diarrhea, increased cholesterol, increased triglycerides, lipodystrophy, increased glucose (sugar), increased liver enzyme levels, increased bleeding in patients with hemophilia, increased liver enzymes. March 14, 1997 Take with food. Can be dissolved in water (if trouble swallowing pill form). Agenerase Amprenavir Twenty-four 50-mg capsules twice a day (to be combined with other HIV medications). Nausea, vomiting, diarrhea or loose stools, taste disorders, tingling feeling (especially around the mouth), depression and mood problems, changes in body fat, high blood sugar or diabetes, diabetes complications, increased cholesterol, or increased triglycerides, severe or life-threatening rash. April 15, 1999 Take with or without food. High fat meals will decrease the absorption of the medication. Do not take additional vitamin E. May need to adjust the dosage when taken with other HIV medications. INTEGRASE INHIBITORS (INIs) Isentress Raltegravir One 400-mg tablet twice a day. Diarrhea, nausea, and headache. In clinical trials, blood tests showed abnormally elevated levels of a muscle enzyme—creatine kinase—in some patients receiving Isentress. Isentress should be used with caution by patients who are at increased risk for muscle problems such as myopathy and rhabdomyolysis, which includes patients using other medications known to cause these conditions. October 12, 2007 Take with or without food. FUSION Fuzeon Enfuvirtide One 90-mg injection twice a day. Skin reactions where Fuzeon is injected can include itching, swelling, redness, pain or tenderness, hardened skin, or bumps; increased risk of bacterial pneumonia; serious allergic reaction (rare). March 13, 2003 Comes as a powder that must be mixed with sterile water in a vial before use. RECPTOR SITE/ENTRY INHIBITOR Selzentry (also known as Celsentri) Maraviroc One 150-mg tablet or one 300-mg tablet or two 300-mg tablets twice a day. Reacts with many other HIV medications, which will affect the regimen. Cough, fever, colds, rash, muscle and joint pain, stomach pain, and dizziness. Less common side effects include cardiovascular problems and liver toxicity. Because Selzentry blocks the CCR5 co-receptor located on some immune system cells, there is a theoretical risk of developing infections and cancers. August 6, 2007 Take with or without food. Effective only against CCR5-tropic HIV.

Viral load measurement

Testing for the amount of HIV in plasma by measuring viral RNA has become a standard component of the management of HIV-infected patients.²³ There are important prognostic implications for the amount of viral load in persons with HIV disease.²⁴ 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.²⁵ Viral load is an important useful marker for judging the effectiveness of various antiretroviral drug interventions.^26,27

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 a particular antiretroviral drug, the HAART regimen may be altered so that the potential for viral suppression is maximized. Changes in the drug combinations used for HAART to respond to viral resistance are referred to as salvage therapy. Like genotypic testing, phenotypic testing may not detect small subpopulations of resistant HIV.²⁸

Researchers continue to work on developing effective HAART components and vaccines. The primary goal of antiretroviral therapy is to achieve prolonged suppression of HIV replication.^23,29 At this time, there are six classes of HIV medications. Two classes of drugs, receptor site inhibitors and fusion inhibitors (FIs), work to prevent HIV from successfully entering the cell. CCR5 inhibitors (CIs) include maraviroc (Selzentry), a CCR5 co-receptor antagonist (receptor site inhibitor). Receptor site inhibitors are the most recently approved class of drugs. FIs such as enfuvirtide (Fuzeon) or T-20 act outside the T cells by blocking the entry of HIV into the cell. T-20 is often used as part of salvage therapy; it is a twice-daily injectable drug with a cost of more than $25,000 per year.

The four 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), an NRTI, was first approved by the U.S. Food and Drug Administration. Since that time, several more NRTI drugs have been approved.³⁰ Other drugs, such as nevirapine and efavirenz, also inhibit the reverse transcriptase enzyme, but they are not nucleoside analogs. These NNRTIs bind to the enzymatic binding pocket of the reverse transcriptase gene and block binding by the nucleosides.³¹ 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.³² INIs, such as elvitegravir or raltegravir (Isentress), are one of the most recently approved classes of drugs. Another drug target for anti-HIV agents is the protease enzyme. The PI drugs are structurally different from other drugs and include agents such as ritonavir, indinavir, nelfinavir, and saquinavir.³³

HAART may be NNRTI or PI based (i.e., NNRTI and PI drugs are used in combination with an NRTI such as AZT). There has been a gradual evolution of pharmacology that has allowed for multiple drugs to be combined into one pill. Thus the number of pills required per day as well as the administration schedule have become increasingly more manageable over recent years. However, drugs from different classes (NRTI, NNRTI, and PI) are typically included in HAART. The current recommendation from the Department of Health and Human Services for a treatment-naïve patient is either one NNRTI and two NRTIs or a PI (boosted with ritonavir) and two NRTIs.²² Because of the rapidly evolving nature of HAART, the reader is advised to consult with the CDC for the most current clinical practice guidelines.

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. Injection site reactions are common with T-20. 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 HAART regimen is modified to mitigate the side effects that may occur with specific drugs.

Current medication regimens can significantly reduce the HIV level not only in the peripheral blood but also in the lymphoid tissue and the central nervous system (CNS).³⁴ The goal of HAART is to reduce HIV viral load to undetectable levels in serum. The greatest challenge with HAART 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.^28,35 In a field that is rapidly changing, specific recommendations for antiretroviral therapy 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 change therapy, and (4) which drugs to change to. When PIs were introduced as a complement to already existing NRTI and NNRTI drugs, the mortality rate of HIV-infected patients and the incidence of opportunistic infections decreased, most likely as a result of the increased use of combination HAART.³⁶ The role of drugs with immunomodulating activity in combination with HAART is also undergoing extensive research.^37,38 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.³⁹

Vaccines

HIV-positive individuals respond less well than do uninfected persons to most vaccines. 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.⁴⁰ Patients with a CD4 count of more than 200 cells/mcL 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.

Vaccination for HIV has the potential to prevent or control disease progression. The development of an effective preventative vaccine for HIV is an area of continuing research. The first human immunizations with the potential AIDS vaccine took place in 1986 in healthy seropositive volunteers in France and Zaire. Low levels of both humoral and cell-mediated immune responses resulted. One conclusion of this study is that booster vaccinations could be effective.⁴¹ Several vaccine candidates have been developed and tested in human phase 1 or 2 trials. To date, at least 13 vaccine candidates have been created with use of different forms of recombinant proteins that target the HIV envelope. Research has found that the vaccine candidates introduced antibodies that rarely neutralized HIV progression, as evidenced by assessment of patient blood counts (i.e., CD4 counts). Furthermore, these recombinant proteins rarely produced a cellular response that would target and destroy cells already infected with HIV.⁴² Currently there is no evidence of a vaccine that produces extended, high-titer neutralization across a variety of HIV strains.⁴² The most recent clinic trial, the Thai Phase III HIV vaccine trial (also known as RV 144), was completed in September 2009. The study incorporated two vaccines, a prime vaccine (ALVAC-HIV) and a booster vaccine (AIDSVAX B/E), which were based on strains found in Thailand, where the clinical trial was conducted. The clinical trial involved over 16,000 volunteers who received either the vaccine combination or a placebo. The clinical trial found that the vaccine regimen was safe and modestly effective, demonstrating that the vaccine combination lowered the HIV infection rate by 31.2% compared with the placebo. The study also found that the vaccine had no effect on the viral load of those volunteers who became infected during the clinical trial.⁴³

Genetic mutation of the virus further complicates attempts to disable it. Genetically similar but distinguishable strains of HIV can exist in one individual. Furthermore, drug-resistant strains of HIV have been identified.⁴⁴ Yet another difficulty with vaccination development is a lack of animal models. Chimpanzees replicate simian immunodeficiency virus, a similar but not identical disease. In addition, an average of 12 years and $231 million is required for a new drug to gain Food and Drug Administration approval. Many major pharmaceutical companies seem wary of the immense research expenses and potential liability risks linked to vaccine development. The result is that smaller biotechnology companies with fewer resources are assailing the complicated problems of HIV infection.¹³ Recent advancements and plans for future clinical trials are largely supported by military or government programs. Researchers are optimistic that the vaccine will induce both humoral and cellular immune responses and have no toxic effects. It will protect against initial infection and retard disease onset in infected individuals.

In summary, as of July 2011 no HIV vaccines have been approved for use; there are clinical trials in process and research in this area is ongoing.

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.⁴⁵ Retrospective demographic research in the United States found that 17.8% of individuals with AIDS had wasting syndrome.^46,47 The ensuing malnutrition contributes to further immunosuppression.⁴⁸ Nutritional consultation is critical for those patients experiencing wasting syndrome and as a preventative measure for those who are HIV positive. 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.⁴⁹

Weight loss or reduction in lean body mass is also a problem for patients using HAART. Comprehensive nutritional intervention is advocated during the early stages of HIV infection to maintain nutritional status. HAART 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, HAART has been linked to a condition identified as 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.⁵⁰ Lipodystrophy is a syndrome that makes the nutritional management of HIV more difficult and may necessitate exercise, pharmacological intervention, and diet modifications.⁵¹

Systemic manifestations

Integumentary system and neoplasms

Cutaneous disorders develop in 64% to 90% of all individuals infected with HIV. Most HIV-induced skin findings develop only when the CD4 count falls below 500 cells/mcL. As the CD4 cell count decreases further, multiple cutaneous disorders may develop.⁵² There are three AIDS-defining malignancies: 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. However, over the past decade the incidence of KS has diminished as a result of the use of more powerful antiretroviral therapy and maintenance of immune status.⁵² KS can involve almost every part of the body, but the most common site of initial KS presentations is the skin or mucous membranes.⁵³ 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.⁵⁴

In KS there is a broad therapeutic spectrum from cryotherapy to systemic chemotherapy.⁵⁵ In NHL, early therapeutic intervention is necessary because of the fast progression of the tumor.⁵⁶ The cervical cancer in HIV-positive women seems to be more aggressive than in HIV-negative women and requires early therapeutic intervention.⁵⁷ The cancer incidence in patients with HIV is reported to be higher among non-black patients.⁵⁸

Several other tumors occur in people with HIV infection: anorectal cancer, lung cancer, malignant testicular tumor, Hodgkin lymphoma, basal cell carcinoma, and malignant melanoma.^56,59 It is beyond the scope of this chapter to detail all aspects of cancer and dermatological 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 workup may be warranted. See Table 31-3 for integumentary conditions associated with HIV.

Musculoskeletal system

Musculoskeletal manifestations of HIV infection are not as common as manifestations seen in other body systems, including the CNS, pulmonary system, and GI tract. Musculoskeletal disorders tend to occur in advanced HIV disease. Knowledge of the different abnormalities that may occur in the musculoskeletal system is crucial to patient management and affects morbidity and mortality. Primary abnormalities are seen as osseous and soft tissue infections, polymyositis, myopathy, and arthritis. Spinal infections such as pyogenic discitis, osteomyelitis, spinal TB, and epidural abscesses are more likely to occur in HIV-positive individuals than in those who are HIV negative. Discitis and osteomyelitis are more common in patients with CD4 counts >200 cells/mcL, whereas spinal TB and epidural abscesses are more common in patients with CD4 counts <200 cells/mcL.⁶⁰ Secondary musculoskeletal complications are often a result of the various compensatory patterns of gait as a result of HIV-related peripheral neuropathy syndrome or the change in biomechanics of the foot and ankle from KS and NHL.⁶¹ These lead to potential spinal changes and back pain.

HIV-positive patients with acute myopathy typically have proximal muscle weakness and elevated creatine phosphokinase levels.⁶² 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.

Arthritis in HIV-positive individuals has a wide spectrum of presentations ranging from mild arthralgias to severe joint disability.⁶³ Arthritides seen in patients with AIDS have 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.⁶⁴ Standardized diagnostic tests and treatments are the same for HIV-positive individuals with musculoskeletal impairments. A key difference to consider is the effect of HAART medications. Side effects of HAART may evoke symptoms that may complicate the differential diagnosis. The HAART drugs taken by HIV-positive patients may limit pharmaceutical treatment options for musculoskeletal conditions, namely immunosuppressant medications. See Table 31-4 for musculoskeletal conditions associated with HIV.

TABLE 31-4 

HIV AND MUSCULOSKELETAL CONDITIONS

CONDITION	SYMPTOMS AND COMMENTS	TREATMENTS
Reactive arthritis, septic arthritis, bursitis	Asymmetrical oligoarthritis or monoarticular arthritis, dactylitis, enthesopathy, joint effusion Most common in the foot and ankle May range from mild to severe Inflammation of synovial fluid, often gram negative

Surgical debridement

Aspiration of fluid from the joint, antibiotics

ROM activities

Idiopathic polymyositis

Bilateral proximal muscle weakness, elevated serum CK levels

Often occurs early in infection

Exact mechanism is still undetermined

Discontinue medication that causes inflammation or irritation of the muscle

Antiinflammatory medications

Corticosteroid medications

Zidovudine-associated myopathy

Causes mitochondrial toxicity

Gradual myalgias, muscle tenderness, proximal muscle weakness, elevated CK levels

Discontinue AZT therapy

CK levels return to normal within 4 weeks (of discontinuing AZT), weakness resolves in 8 weeks

Pyomyositis

Solitary or multiple muscle abscesses that are not formed by local extension from superficial subcutaneous tissue

Acute, severe muscle pain with or without erythema, fever, edema

Elevated ESR and CK levels

Pathogen is most often Staphylococcus aureus

Differential diagnosis includes muscle strain, contusion, hematoma, cellulitis, deep venous thrombosis, osteomyelitis, septic arthritis, and neoplasm

If not treated, septic shock and death can result in 3 weeks

Open drainage or debridement of the site

Antibiotic therapy

Psoriatic arthritis

Cutaneous manifestations (macropapules on the knees, elbows, scalp and trunk), nail changes, arthritic changes or deformities, soft tissue swelling, juxtaarticular erosions, osteopenia, osteolysis

Five types: asymmetrical oligoarthritis, symmetrical polyarthritis, dominant desquamative interstitial pneumonia, arthritis mutilans, and sacroiliitis or spondylitis without peripheral involvement

Synovial fluid usually contains 7000 to 15,000 white blood cells/mcL

NSAIDs

Second-line agents (gold, methotrexate, and azathioprine)

Intraarticular steroid injection (every 4 to 6 months)

ROM activities

Reiter syndrome

Urethritis, conjunctivitis, and arthritis, nail involvement with subungual hyperkeratosis, circinate balanitis, keratoderma hemorrhagica, oral ulcers, uveitis, AIDS foot, weight loss, malaise, lymphadenopathy, and diarrhea

Severe course of persistent and erosive polyarthritis, fevers, and enthesopathies, which responds poorly to treatment or has a mild and self-limited course

Common enthesopathies include Achilles tendinitis, lateral or medial epicondylitis, rotator cuff tendinitis, and de Quervain tenosynovitis; axial skeleton involvement is rare

Broad-based gait and stiff ankles with weight bearing through the lateral margins of the feet because of the painful heel; patients may become severely disabled and wheelchair bound

NSAIDs

Second-line agents (gold, methotrexate, and azathioprine)

Patients usually obtain relief after 5 to 7 days of therapy

Intraarticular steroid injection (every 4 to 6 months)

Methotrexate, other immunosuppressive agents, and phototherapy should be used only with extreme caution

Early physical therapy and splinting of affected joints as needed to prevent atrophy and contractures

Diffuse infiltrative lymphocytosis syndrome (DLS)

Massive parotid enlargement, xerostomia, and lymphocytic hepatitis caused by CD8 lymphocytic infiltration of the liver

Xerophthalmia (dry eyes), xerostomia (dry mouth), salivary gland enlargement, and arthralgias

Extraglandular features may be pulmonary, neurological, gastrointestinal, renal, or musculoskeletal

Symptomatic treatment with artificial saliva and tears

Antibiotics to address recurrent sinus, middle ear, and oral cavity infections

Immunosuppressive therapy should be used only when patients are in life-threatening situations such as pulmonary insufficiency or renal disease

Corticosteroids can be used for extraglandular features

Radiotherapy to reduce the enlarged parotid gland

Avascular necrosis or osteonecrosis

Results from direct or indirect damage to the vascular supply of the affected bone, leading to in situ death of subchondral bone

Most common sites are the femoral head followed by the humeral head; may occur in other locations including the wrist (scaphoid [Preiser disease] or lunate [Kienböck disease]), knee, and ankle

Deep, throbbing, intermittent pain that may be insidious or sudden in presentation and, in later stages, a loss of motion

Early osteonecrosis may be treated by minimizing the forces across the joint, either through avoiding weight-bearing activity (lower extremity) or through greatly limiting activity such as lifting and carrying (upper extremity)

Advanced stages require surgical intervention in an attempt to restore vascularity, provide stabilization, or replace the joint

ROM activities

Hypertrophic osteoarthropathy

Systemic disorder affecting bones, joints, and soft tissues, often develops in patients with PCP

Severe pain in the lower extremity, digital clubbing, arthralgias, nonpitting edema, periarticular soft tissue involvement of the ankle, knees, and elbows; skin over the affected areas is glistening, edematous, and warm; chronic erythema, paresthesias, and hyperhidrosis may be noted in the hands and feet

Radiography reveals extensive periosteal reaction and subperiosteal proliferative changes in the long bones of the lower extremity; bone scan demonstrates increased uptake along the cortical surfaces

Treatment of PCP usually alleviates this condition

Surgical or chemical vagotomy or radiation therapy may be necessary in refractory cases

Acute symmetrical polyarthritis

Acute symmetrical polyarthritis exclusive to HIV-infected patients; resembles rheumatoid arthritis, develops in the small joints of the hand

Characterized by ulnar deviation of the digits and swan neck deformities

Acute onset and negative rheumatoid factor test result help differentiate it from rheumatoid arthritis

Radiographic results also mimic those of rheumatoid arthritis, with periarticular osteopenia, joint-space narrowing, and marginal erosions

Gold therapy is effective treatment

ROM activities

HIV-associated arthralgia

Asymmetrical, oligoarticular arthritis exclusive to HIV-infected persons; usually occurs in the late stages, but may occur in any stage

Characterized by an acute onset of severe pain and disability, predominantly in the large joints such as the knees or ankles

Self-limiting; may be mild to moderate severity; usually lasts a few weeks to 6 months

Synovial fluid commonly contains only 50 to 2600 white blood cells/mcL

Radiography may show diffuse osteopenia but without erosive changes; serum is negative for HLA-B27 and rheumatoid factor

Synovial biopsy reveals a chronic mononuclear cell infiltrate

Symptomatic relief with NSAIDs

Intraarticular corticosteroid injections

ROM activities

AZT, Zidovudine; CK, creatine kinase; ESR, erythrocyte sedimentation rate; NSAIDs, nonsteroidal antiinflammatory drugs; PCP, Pneumocystis jiroveci pneumonia; ROM, range of motion.

Cardiopulmonary system

Pulmonary diseases continue to be important causes of illness and death in patients with HIV infection, but changes in therapy and demographics of HIV-infected populations are changing 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.⁶⁵ 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 TB and bacterial pneumonia.

Anti-Pneumocystis prophylaxis has reduced the incidence of and mortality from 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.^66,67 Adjunctive corticosteroid therapy has improved the outlook for respiratory failure.⁶⁵ Multiple studies have shown that the use of corticosteroids in HIV-positive patients in acute respiratory failure has not increased the risk for the development of opportunistic infections.⁶⁸

Mycobacterial infections in HIV-infected individuals usually manifest as either MAC infection or TB.⁵ Steadily increasing incidence of infection by Mycobacterium tuberculosis is likely the result of two factors: better medical management of HIV as a whole and the development of multidrug-resistant strains of mycobacteria. MAC infection tends to appear late in the course of HIV infection. Initial infection involves the GI and pulmonary tracts and eventually disseminates throughout the body. This disorder probably is caused not by latent reactivation of the organism but rather by primary infection by ingestion or inhalation.⁶⁹ 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 HIV-positive patients, but extrapulmonary infection, especially in lymph nodes and bone marrow, occurs in up to 60% of these individuals as well.^66,69–71 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.^66,71 The risk of infection in health care personnel and in the general 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.⁶⁶ 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.

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.⁷² However, an individual who is immunosuppressed becomes more vulnerable to symptoms of infection with CMV. Predominant consequences of HIV-CMV co-infection are unilateral or bilateral deficits in visual acuity, visual field cuts, and blindness.

Although most other organ system involvement has been extensively described in studies and reviews, cardiac complications related to HIV infection have remained less characterized. Most studies have described cardiac problems as postmortem findings, although some clinical series have been reported. It is now clear that cardiac involvement in people living with HIV infection is quite common. Pericardial effusion and myocarditis are among the most commonly reported cardiac abnormalities. Cardiomyopathy, endocarditis, and coronary vasculopathy have also been reported. It is now apparent that HIV infection itself, the medical management of HIV disease, and secondary opportunistic infections can all affect the myocardium, pericardium, endocardium, and blood vessels.^72,73 Cardiovascular risk in HIV-positive patients depends on several factors: direct and indirect vascular effects of chronic exposure to the virus, metabolic effects from prolonged HAART, the normal aging process (important to consider given the increased life expectancy of HIV-positive patients), and other cardiovascular risk factors (such as diet and genetics).⁷⁴

Body fat changes and lipid abnormalities have been reported in individuals with HIV disease.⁷⁵ Known as lipodystrophy or fat redistribution syndrome, these body fat and metabolic changes have been connected to PI use.⁷⁶ It is estimated that 50% of HIV-positive individuals taking HAART develop these metabolic conditions.⁷⁷ 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 particular 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.^78,79 The increased abdominal growth is characterized by a redistribution and accumulation of fat in the central visceral areas of the body.^79,80 Corresponding symptoms include GI discomfort, bloating, distention, and fullness.⁸⁰

In addition to visible signs and symptoms, adverse changes in lipid, glucose, and insulin levels have been reported.⁸¹ A number of studies have revealed hyperlipidemia to be present in HIV-positive patients, many of whom, but not all, were undergoing PI therapy.⁸²

To date, the exact cause of lipodystrophy has not been determined, but two main theories have been hypothesized. Each is still in the process of being studied.^75,83 As individuals live longer with HIV disease, they are at greater risk for development of cardiac disease. Therapists need to be apprised of various changes in laboratory results and signs and symptoms of 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:

See Table 31-5 for effects of HIV treatment on cardiovascular factors and Table 31-6 for cardiovascular risk factors associated with HIV.

Lipid metabolism (LDL-C) No evidence of direct medication effects on LDL-C. Lipid metabolism (triglycerides) Increases in late infection with viral suppression; decreased in early studies of AZT use. Glucose metabolism (insulin sensitivity) Glucose metabolism (insulin secretion) Some PIs may decrease insulin secretion. Glucose metabolism (fasting glucose) Some PIs may increase glucose production. Glucose metabolism (glucose tolerance) With HAART there may be higher rates of impaired glucose tolerance. Glucose metabolism (diabetes) Higher prevalence of type 2 diabetes associated with certain PIs and NRTIs. Body composition (lean body mass) No consistent evidence of direct medication effects. Body composition (peripheral fat ) Subsequent depletion of subcutaneous fat in the face, arms, legs, and buttocks is associated with some NRTIs. Body composition (visceral fat) Decreased minimally when untreated; increases with effective HAART. Preserved or increased visceral fat in some patients on HAART. Renal function (renal disease) Some HAART may cause impaired renal function.

Neurological system

The neurological manifestations of HIV disease are numerous and involve the autonomic nervous system (ANS), CNS, and peripheral nervous system (PNS).⁸⁴ Over the course of the disease, up to 70% of patients have some form of neurological symptom.⁸⁵ Significant progress in understanding and treating the neurologically involved HIV patient has been made over the past decade.⁸⁶ However, HIV continues to affect every division of the human nervous system (Box 31-2). HIV-positive infants show early, catastrophic encephalopathy, loss of brain growth, motor deficits, and cognitive dysfunction.⁸⁷ Unfortunately, neurobehavioral dysfunction in early pediatric AIDS remains unchanged after therapy. Dementia develops in some adult patients in spite of the multidrug therapies, and other patients have subtle neurobehavioral changes that diminish the quality of their prolonged lives. Thus 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). Studies are demonstrating similarities between factors that predispose HIV-positive patients to HANDs and the risk factors of Alzheimer dementia, suggesting the potential for a common pathological mechanism.⁸⁸ Evidence has shown that HIV-infected monocytes are carried across the blood-brain barrier and infect the macrophages and microglia in the CNS.^89,90 HIV enters the CNS early, yet HANDs often do not occur until advanced stages when the patient is categorized as having AIDS. 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 current HAART medications have poor CNS penetration, HANDs continues to pose significant challenges for advanced HIV/AIDS patients.⁹¹ See Table 31-7 for neurological conditions associated with HIV.

CONDITION COMMENTS AND SYMPTOMS PROGNOSIS AND TREATMENT AIDS dementia complex (ADC; HIV-associated encephalopathy) CNS lymphomas Prognosis is poor owing to advanced and increasing immunodeficiency. Cryptococcal meningitis Cytomegalovirus (CMV) infections Herpesvirus infections Neurosyphilis Progressive multifocal leukoencephalopathy (PML) Psychological and neuropsychiatric disorders Stroke and hemorrhage Toxoplasmosis Vacuolar myelopathy Primary central nervous system (PCNS) lymphoma Meningitis Treatment and prognosis vary by the specific cause of meningitis, severity at presentation, delay from symptom onset to treatment, and status of immunosuppression. Tuberculosis meningitis Distal sensory polyneuropathy Inflammatory demyelinating polyneuropathy (IDP) Mononeuritis multiplex Polyradiculopathy Myopathy

Autonomic nervous system.

Dysfunction of the ANS has been associated with HIV infection. This has implications for overall function and the design of a rehabilitation program for people living with HIV disease. In one study, individuals with the greatest ANS involvement had dementia, myelopathy, and sensory peripheral neuropathy. Variations in heart rate, including resting tachycardia, were common. Abnormal blood pressure readings were identified in response to isometric exercise and positional changes (sit to stand and tilting).⁹²

Central nervous system.

HIV enters the CNS during the early stages of the disease and is hypothesized to traverse the blood-brain barrier during the initial acute primary infection stage. Although the initial CNS invasion by HIV is asymptomatic in most individuals, affective and cognitive deficits may develop.⁹³ It is not possible in this context to discuss the neuropathological features of each of the many secondary infections and neoplasms of HIV illness. It is important to realize, however, that the clinical manifestations of these pathological processes overlap with one another and with the signs and symptoms of primary HIV infection of the CNS; lesions of the CNS can be the site of more than one opportunistic disease process simultaneously. In Table 31-8, a wide variety of organisms or conditions responsible for the neurological manifestations associated with HIV infection are listed. These include primary and secondary viral, protozoan, fungal, and Mycobacterium infections, as well as neoplasms and iatrogenic conditions. Infectious processes may cause large lesions in the brain, such as meningitis, encephalitis, or both. Such infections cause neurocognitive impairments that develop as dementia, amnesia, or delirium.⁹³ Thirty percent to 40% of healthy adults have contracted toxoplasmosis, caused by Toxoplasma gondii.^34,94 Unchecked by the immune system, toxoplasmosis results in CNS dysfunction—namely, altered cognition, headache, focal neurological deficits, encephalitis, and seizures. Cerebellar disorders associated with HIV infection are typically the result of discrete cerebellar lesions resulting from opportunistic infections such as toxoplasmosis and progressive multifocal leukoencephalopathy or primary CNS lymphoma.⁹⁵ CNS lymphoma results in cognitive dysfunction and presentation of fever, focal neurological impairments, headache, seizures, and motor deficits.⁹³

None Toxoplasmosis—Toxoplasma gondii, a protozoan found in air, water, soil, and some cats and other animals. Most often acquired by ingestion of uncooked infected lamb or pork, unpasteurized dairy products, raw eggs, or vegetables. Mothers can give it to unborn children. Other human-human transmission does not occur. Produces lesions in the CNS; may also involve heart and lungs Fever, chills, headache, visual disturbances, lethargy, confusion, hemiparesis, seizures None Cryptosporidiosis—Cryptosporidium, a protozoan primarily acquired through oral contact with feces of an infected animal, or oral sexual contact with an infected person GI tract Copious diarrhea, abdominal pain, anorexia, nausea, vomiting, dehydration, weight loss, weakness, fever Isosporiasis—Isospora belli, a protozoan primarily acquired through eating uncooked beef or pork or through oral sexual contact with an infected person GI tract Diarrhea, abdominal pain, nausea, vomiting, anorexia, weight loss, weakness, fever Trimethoprim-sulfamethoxazole: see under PCP—P. jiroveci Mycobacterium avium-intracellulare infection—M. avium-intracellulare, a bacterium found in soil, water, animals, eggs, and unpasteurized dairy products and other foods. Infection is atypical and noncommunicable. Disseminated Fever, malaise, night sweats, anorexia, diarrhea, weight loss Gloves and gown or apron when handling wound drainage Candidiasis—Candida albicans, a fungus that inhabits the oropharynx, vagina, large intestine, and skin, causing no harm as long as immunity remains undamaged; may occur as a secondary infection in conjunction with herpes simplex virus lesions. Anywhere skin or mucous membrane is damaged, including through intravenous therapy and pressure monitoring sites Thrush, esophageal, perianal irritation, vaginitis, proctitis; inflammation around fingernails can be disseminated None Cryptococcosis—Cryptococcus neoformans, a fungus found in air, water, soil, raw fruits and vegetables, and pigeon droppings found on window ledges and nesting places; acquired by inhalation. CNS, lungs; can be disseminated Altered cognition, low-grade fever, headache, nausea, vomiting, meningeal signs None CMV infection—cytomegalovirus, an organism found in saliva, semen, cervical secretions, urine, feces, blood, breast milk. It causes problems only when immunity is compromised. Disseminated Fever, profound fatigue, muscle and joint aches, night sweats, impaired vision, cough, dyspnea, abdominal pain, diarrhea Ganciclovir: leukopenia, bone marrow depression, elevated liver enzymes, edema, nausea, muscle aches, headaches, anorexia, disorientation, rash, phlebitis Herpes simplex virus (HSV) infection—HSV-1 is spread by contact with infected oral secretions. HSV-2 is spread by contact with infected genital secretions. Patient can spread either variety by touching lesions then touching other body parts. Mouth, perianal area; can be disseminated Painful burning, itching vesicular lesions; sometimes colitis, pericarditis, esophageal infection Acyclovir: rash, diarrhea, light-headedness, headache, nausea, vomiting, thirst, fatigue Progressive multifocal leukoencephalopathy (PML)—JC virus; transmission routes unclear Brain Impaired speech, vision, and thought; ataxia and limb weakness; advanced disease can cause profound dementia No known effective treatment None

Peripheral nervous system.

Possible neurological complications associated with HIV disease that may affect the PNS include meningitis, ataxia, myelopathy, and encephalitis. PNS diseases have been reported in up to 50% of HIV-infected individuals, resulting in distal polyneuropathy, Guillain-Barré syndrome, and mononeuropathy.¹⁰²

Distal symmetrical polyneuropathy (DSP) is the most common form of neuropathy in HIV infection. The most frequent complaints in DSP are numbness, burning, and paresthesias in the feet. These symptoms are typically symmetrical and often so severe that patients have contact hypersensitivity and gait disturbances. Involvement of the upper extremities and distal weakness may occur later in the course of DSP. Neurological examination shows sensory loss to pain and temperature in a stocking-glove distribution, increased vibratory thresholds, and diminished ankle reflexes compared with knee reflexes.^85,103 Patients with AIDS frequently have concurrent CNS disorders and neuropathy, characterized by hyperactive knee reflexes and depressed ankle reflexes.

The incidence of DSP increases with advancing immunosuppression, in parallel with decreased CD4 counts.¹⁰⁴ Thirty-five percent of patients with AIDS may have electrophysiological or clinical abnormalities.¹⁰⁵ Furthermore, pathological evidence of DSP is present in almost all patients who die of AIDS.¹⁰⁶ Various theories regarding the mechanism of DSP have been proposed. It was formerly thought that direct HIV invasion of the nervous system caused DSP⁹⁴; however, most investigators now believe that this is not the sole cause.¹⁰⁴ A “dying-back” neuropathy affecting all fiber types, with prominent macrophage infiltration of the peripheral nerve, has been described.¹⁰⁶ Additional theories include HAART drug toxicity, neurotoxic effects of cytokines, toxicity of HIV proteins, and mitochondrial damage.¹⁰⁷ Cytokines, tumor necrosis factor, and interleukin-1 have been identified in the peripheral nerves of patients with AIDS.¹⁰⁸

Balance and postural mechanisms.

Balance disturbances may be seen with HIV involvement of either the CNS or the PNS. Polyneuropathy caused by AZT (AZT polyneuropathy) and CMV, which is a common pathogen in AIDS (inflammatory polyneuropathy), may manifest in the form of a generalized asymmetrical demyelination and chronic denervation of muscles.¹⁰⁹ Demyelination and denervation of nerves that supply postural muscles may weaken such muscles and result in balance problems (e.g., distal pain, paresthesia, numbness, or core weakness). It is also possible that, apart from muscle demyelination and denervation, the pathological process, which also includes macrophage infiltration of neural structures, could spread to affect the vestibular neural complex of the inner ear, which is important in the maintenance of both static and dynamic balance. Our clinical experience shows that sensory changes are common in the lower limbs of neuropathic HIV/AIDS patients. The balance problems of these patients are likely to be connected to a lack of adequate proprioception from the legs during stance, and it is well known that diminished sensory information makes gait control more difficult. Refer to Chapter 22 for a discussion of balance dysfunction.

Peripheral neuropathy weakens the neuromuscular system and causes a limitation in functional activities. These effects on the neuromuscular system manifest in disturbances of postural control. An appropriate posture should be regarded as the starting position for a functional activity. However, compromise of the postural pattern is so characteristic of HIV peripheral neuropathy that it is diagnostic for HIV-1 infection.¹¹⁰ The neurological abnormality resulting from peripheral neuropathy in HIV/AIDS produces postural disturbances¹¹¹ that may take various forms that worsen with the severity of the neuropathy¹¹² and compromise functional activity at various levels. This means that as the condition of HIV/AIDS patients deteriorates, balance deficits may increase.

According to Husstedt and colleagues,¹¹³ peripheral neuropathy in HIV disease progresses much more rapidly than that associated with diabetes or hereditary polyneuropathies. Again, because of demyelination as the HIV infection progresses, distal symmetrical peripheral neuropathy increases, resulting in a depression of certain motor functions such as gait and manual dexterity, and a worsening of the condition is caused by demyelination.¹¹³ There is therefore a need to treat HIV neuropathy as soon as it is diagnosed, to avoid complications that lead to impairments in functional mobility.

One group⁶¹ has identified peripheral neuropathy and its complications as causes of functional limitations in individuals with HIV disease. A patient who, for instance, has balance impairment resulting from peripheral neuropathy may not function effectively with ADLs. Functional impairments may impede a patient’s ability to return to gainful employment. For individuals with HIV disease, peripheral neuropathy and its resulting pain may be a limiting factor in the ability to return to work. Any intervention that can aid in the reduction of functional limitations should be incorporated into the rehabilitation plan of care.

Pain

A factor closely related to HIV neuropathy is pain. Pain is one of the most prominent and distressing symptoms in patients with HIV disease, and it has a significant effect on quality of life and psychological state. Pain may affect patients at any stage of the disease process; however, it is more frequent during the advanced stages. The occurrence of pain during HIV infection varies from 30% to 80%. Pain is the result of a complex process that involves psychological and neurophysiological mechanisms, and therefore it should be assessed with use of sensitive tools that examine its multidimensional nature. One model that evaluates the evaluative, affective, and sensory aspects of pain is the McGill Pain Questionnaire. This assessment tool is useful in evaluating HIV disease–related pain because different causes and nonsensorial factors related to the disease often make clinical assessment of pain difficult.¹¹⁴

Most HIV patients require various pain treatment interventions. Distal symmetrical peripheral neuropathy has been shown to be the most common peripheral neuropathy complaint in patients with HIV-1 infection.115–117 Peripheral neuropathy is one of the most common types of pain in HIV-infected men,¹¹⁸ and peripheral neuropathies occur in as many as 40% to 60% of patients with HIV disease. Peripheral neuropathy is the most prevalent neurological complication associated with HIV. CNS or PNS involvement has been found in 30% to 63% of patients across the arena of HIV and is often related to antiretroviral therapy.¹¹⁹ When neuropathy results in distal painful paresthesia, imbalance in stance and gait may result from compensatory measures aimed at relieving pain in dynamic standing activities. Postural compensations may further exacerbate musculoskeletal, cervical, thoracic, or lumbosacral back pain.

Pain management is a critical part of the overall care of individuals with HIV disease. Pain is the second most common reason for hospitalization of patients with AIDS.¹²⁰ A study of 72 AIDS patients found that 97% had pain related to the disease process.¹²¹ Newshan and Wainapel,¹²¹ who surveyed 100 patients who had pain associated with AIDS, showed that the two reported pain types were abdominal and neuropathic pain. In a longitudinal study of HIV-positive men, painful peripheral neuropathy was one of the most common types of pain.¹¹⁸

DSP results in painful paresthesias that are challenging to treat with pharmacological interventions. Oral gabapentin and cutaneous lidocaine patches are often prescribed to manage pain associated with peripheral neuropathy. Clinical experience shows that conventional transcutaneous electrical nerve stimulation may exacerbate or relieve peripheral pain in patients with HIV infection. Another consideration for treatment is low-voltage electroacupuncture.¹²² Manual therapy to improve ankle and foot range of motion along with other compensatory areas is recommended for pain management and return to function. (See Chapters 32 and 39 for additional information.)

Psychopathology

Medical and neuropsychiatric sequelae of HIV infection present a spectrum of diagnostic and treatment challenges to health care practitioners. Both HIV infection and the various opportunistic infections that manifest in patients as the result of an immunocompromised state can affect the CNS. Epidemiological studies indicate that greater than 60% of HIV-positive individuals will experience at least one major psychiatric disorder during the course of their infection. Depression is the most common disorder, closely followed by anxiety and substance abuse disorders.¹²³ Therefore therapists need to be familiar with the diagnosis and management of HIV infection–related medical and psychiatric disorders. These disorders have a great impact on the outcomes of rehabilitation.

Careful consideration of psychological function is warranted during clinical encounters with HIV-infected persons. AIDS-related psychopathologies mimic many previously described consequences of primary HIV infection, opportunistic infections, and drug side effects. These psychiatric complications can be affective or organic. Indicators include disturbances in sleep and appetite patterns, diminished memory and energy, psychomotor retardation, withdrawal, apathy, and emotional liability. Anxiety disorders (particularly post-traumatic stress disorder), adjustment reactions, reactive and endogenous depressions, and obsessive disorders frequently result.124–126 Refer to Chapter 6 for additional recommendations regarding psychological adaptation and adjustments to nervous system dysfunction.

With use of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, one study found Axis I disorders (excluding substance abuse) in 61.9% of the subjects.¹²⁷ Indeed, the virus’s affinity with subcortical structures of the CNS that regulate affect and mood supports research indicating a prevalence of manic episodes that is 10 times higher than in the general population.¹²⁸ Manic episodes have been identified at all stages of the disease process and may also occur in response to AZT therapy.^16,46,129 When associated with HIV infection, mania appears to be secondary to structural CNS changes.^130,131 Described manic episodes generally respond well to psychiatric medications and may not recur.^46,132–134

Analyses of new-onset psychosis among HIV-positive individuals yielded the following information. Psychotic episodes are preceded by a period (days to months) of affective and behavioral changes.¹³⁵ Admitting diagnoses to psychiatric units included “undifferentiated schizophrenia, schizophreniform disorder, ‘reactive psychosis,’ atypical psychosis, depression with psychotic features and mania.”¹³⁵ Some psychiatric diagnoses were revised during the course of hospitalization to “AIDS encephalitis, cryptococcal meningitis, or ‘organic psychosis.’”¹³⁶ Eighty-seven percent of the subjects in one study displayed delusions that were usually persecutory, grandiose, or somatic. Affective disturbances were present in 81% of the subjects. Hallucinations and thought process disorders were each prominent in 61% of patients. Several subjects received the diagnosis of AIDS during their psychiatric hospitalization.¹³⁶

Remarkable progress has been made in recent years in the therapeutics of HIV-associated dementia. Viral replication in and outside the CNS has been reduced by HAART. This has resulted in partial repair of cellular immune function with improvement in, and prevention of, neurological deficits associated with HIV disease.¹³⁷ Extensive use of PIs is associated with dramatic declines in overall mortality and morbidity, including HIV-associated dementia.^37,138

Neuropathological abnormalities seen in the brain tissue of patients with HIV-associated dementia are usually diffuse and predominantly localized to the white and deep gray matter regions. Myelin pallor and inflammatory infiltrates composed of macrophages and multinucleated giant cells are the hallmarks of this disease process, although a spectrum of lesions has been identified from encephalitis to leukoencephalopathy.^139,140 The characteristic clinical feature of HIV-associated dementia is disabling cognitive impairment, often accompanied by behavioral changes, motor dysfunction, or both.¹⁴⁰ Degrees of impairment have been recorded, and a five-part staging system was subsequently developed.^141–143 Motoric manifestations of AIDS dementia complex include gait disturbances, intention tremor, and abnormal release of reflexes.

Differentiation between psychiatric and physiological manifestations is complicated. Psychiatric and organic disorders are initially indistinguishable on the basis of behavior and may exist concurrently. Furthermore, other primary disease processes and drug reactions imitate psychopathological conditions. Differentiation is nonetheless essential because many disorders respond well to established therapies, both psychological and pharmacological, once differential diagnoses have been established. Awareness of the intricate interplay of all factors is essential for competent rehabilitative efforts for those infected with HIV.

Pediatric HIV infection

Pediatric HIV infection differs from that most commonly seen in adults. Symptoms develop much earlier in pediatric patients compared with adults. Children infected with HIV may be classified as “rapid progressors” or “slow progressors.” Rapid progressors are children infected with HIV who manifest symptoms within the first 12 to 24 months of life. These children progress quickly to AIDS-defining conditions and have a rapid decline in CD4 count. Children who are slow progressors have a more gradual progression of symptoms and are likely to show evidence of immune system compromise by 7 to 8 years of age. A small percentage of children remain healthy and have only nominal or no symptoms of the disease and a normal to slightly decreased CD4 count through 9 to 10 years of age.¹⁴⁴

The prediction of 6 million pregnant women and 5 to 10 million children infected with HIV-1 by the year 2000¹⁴⁵ may have been an underestimate. An accurate understanding of the timing of HIV transmission from mother to fetus is important for the design of intervention strategies. The AIDS Clinical Trial Group Study (ACTG) 076 trial, which included treatment from the fourteenth week of gestation in women with CD4 counts of more than 200/mm³, prompts other considerations.¹⁴⁶ Onset of HIV-1 infection in children has a wide spectrum of clinical manifestations.¹⁴⁷ Thus prevention of transmission from mother to fetus via HAART is a critical component of managing this worldwide epidemic.

Pediatric HIV is neurotrophic in nature in that the virus most often initially affects the CNS rather than the PNS. As the virus spreads, pediatric HIV patients can have CNS disorders that include encephalopathy, pyramidal tract signs, receptive and expressive language difficulties, cognitive deficits, psychomotor impairments, and upper respiratory infections.¹⁴⁴ Neuroimaging shows HIV has an influence on neurological function in the basal ganglia, frontal cortex, and other connecting structures in the CNS. Studies also support that there is an environmental component which contributes to developmental and behavioral issues in HIV-positive children.¹⁴⁸

In the first year of life, severe immunodeficiency develops in 15% to 20% of pediatric patients with serious recurrent infections or neurological dysfunction, whereas in school-age children the disease progresses more slowly and the risk for development of HIV-related encephalopathy becomes less.¹⁴⁹ Some infants have features of severe immunodeficiency, whereas others have nonspecific findings, such as hepatosplenomegaly, failure to thrive, unexplained fever, parotitis, and recurrent gastroenteritis. Adenopathy is common, and salivary gland enlargement occurs more frequently than in adults. Otitis media and measles, despite immunization, are also more frequent complications in children.^56,81 Cardiac involvement in children with HIV infection is a well-known entity and occurs clinically more often in patients with advanced disease.¹⁵⁰

Studies have shown that children with HIV demonstrate behaviors often associated with attention-deficit/hyperactivity disorder (ADHD) including impulsivity, hyperactivity, difficulty attending, and decreased ability to focus on stimuli. In one study, the most common behavioral issues were psychosomatic disorders (28%), learning disorders (25%), hyperactivity (20%), impulsive-hyperactive disorder (19%), conduct problems (16%), and anxiety (8%); standardized intelligence scores were lower compared with established population norms. Hyperactivity was more common in children with a Wechsler IQ lower than 90, anxiety issues were more common in children older than 9 years, and conduct disorders were more often seen in children with CD4 counts less than 660 cells/mcL.¹⁴⁸

Children are susceptible to disorders seen in adults—herpesvirus infection, pneumonia, toxoplasmosis, meningitis, and encephalitis. HIV encephalopathy is noted to have the most serious side effects because of its progressive deteriorating pattern and associated CNS abnormalities,¹⁷ although static encephalopathy can be characterized by severely delayed cognitive functioning and neuromotor skills without deterioration.¹⁵¹ Manifestations in children include cerebral atrophy, ataxia, rigidity, hyperreflexia, and the inability to achieve or sustain developmental milestones. Although the HIV neurodevelopmental involvement causes a prognostic worsening, most studies of pediatric cases of neuro-AIDS demonstrate that an early diagnosis followed by adequate antiretroviral therapeutic regimens can lead to significant, even if temporary, improvement.¹⁴⁹

Rehabilitation of the pediatric patient requires a multidisciplinary approach to meet the medical, emotional, and psychosocial needs of these children and their families. Children are encouraged to give form to their psychological experiences through play, writing or telling stories, and creating works of art.¹⁵²