Rehabilitation of the Individual with HIV

Stephen F. Levinson

Steven M. Fine

INTRODUCTION

The quest for effective treatment, prevention, and cure of the acquired immunodeficiency syndrome (AIDS) has resulted in one of the most concentrated research efforts in the history of medicine. Since its discovery in the early 1980s, the human immunodeficiency virus (HIV) has become one of the most studied of human pathogens. Although an outright cure for AIDS still seems to be a distant dream, developments have been breathtaking and, as of the time of this writing, the possibility of controlling the progression of HIV infection, preventing the decline in immune function that leads to AIDS, and enabling the reconstitution of the immune system destroyed by the virus, is within grasp. An effective vaccine, however, remains elusive.

HIV is important to the field of rehabilitation for two reasons: its occurrence in traditional rehabilitation patients and it can, in and of itself, result in disability. HIV is among the differential diagnosis of many disorders commonly seen in rehabilitation settings. In patients with known HIV infection, rehabilitation professionals need to be familiar with the many chemotherapeutic agents commonly used for treatment and with their side effects and drug interactions. This last task is particularly daunting given the accelerated process for U.S. Food and Drug Administration (FDA) review and approval of new treatments.

This chapter emphasizes the nature of HIV and the many ways that it can cause disability. Current medical treatment strategies are also discussed. However, the discussion is not intended to be comprehensive, and interested readers are urged to follow the literature closely and keep up to date in this rapidly evolving field. The medical management of HIV disease and its complications should be left to experts. Rehabilitation strategies used to manage functional impairments typical of those found in association with HIV, such as spinal cord injury, brain injury, neuropathies, and rheumatologic disorders, however, are similar to those used in disability resulting from other causes, as discussed elsewhere in this book.

HIV-RELATED DISABILITY

The full extent of disability resulting from HIV is unknown. One of the earliest studies attempting to evaluate this, the NIH retrospective study, looked only at individuals with AIDS who were involved in research protocols and were referred for various rehabilitation interventions (1). A more comprehensive prospective study of disability in a population of men with HIV was obtained as part of the AIDS Time-oriented Health Outcome Study (ATHOS) (2,3). Of those individuals with AIDS, more than 50% reported difficulty with one or more instrumental ADLs, such as grasping and driving, nearly 30% with basic ADLs, such as bathing and dressing, and more than 40% with basic mobility. Even among symptomatic seropositive individuals without AIDS, nearly 30% reported difficulties with instrumental ADLs, more than 10% with basic ADLs and 15% with basic mobility. With the introduction of highly active antiretroviral therapy (ART, formerly HAART), it has become possible to control and even reverse the progression of HIV. Although functional abilities generally improve with treatment, some degree of functional impairment often remains, and continued functional decline has been reported (4, 5, 6, 7, 8). Quality-of-life issues have also become more significant as survival improves (9, 10, 11).

NATURAL HISTORY OF HIV

Pathogenesis

HIV type I infection (HIV-1), the most prevalent form of the virus, results in the destruction of CD4-positive lymphocytes, leading to a decline in their numbers. In acute primary infection, HIV-1 replicates briskly and viral titer rises rapidly (12, 13, 14). Within 1 week of onset, 10⁵ to 10⁷ infectious particles per microliter of plasma can be measured (15,16). Fifty to seventy percent of patients experience a clinical syndrome, which may include fever, rash, sore throat, lymphadenopathy, splenomegaly, myalgias, arthritis and, rarely, meningitis.

Within a few weeks to months, seroconversion occurs and HIV-1 antibodies can be measured by the enzyme-linked immunosorbent assay (ELISA) and Western blot tests. Rapid viral replication persists, however, in the bloodstream, lymphoid tissue, and central nervous system (CNS) leading to a high turnover of infected cells (13,17). A steady state of plasma HIV ribonucleic acid (RNA) level is established within 6 to 12 months of seroconversion, and measurements of the viral load are prognostic (18,19). Levels of 10⁶ HIV-1 RNA copies or greater per microliter of blood correlate with rapid
progression over a few years, 10³ to 10⁵ with progression in 8 to 10 years and less than 10³ with nonprogression (20). Unfortunately, rapid viral turnover and mutation lead to the appearance of resistant strains if viral suppression is not complete (21, 22, 23).

TABLE 47.1 Classification of HIV

CD4 Cell Count	Group A: Asymptomatic, Acute HIV, or Generalized Lymphadenopathy	Group B: Symptomatic, not A or C	Group C: Indicator Conditions Present
≥500/mm³	A1	B1	C1^*
200-499/mm³	A2	B2	C2^*
<200/mm³	A3^*	B3^*	C3^*
^*Indicates the presence of AIDS.

Classification

The Centers for Disease Control and Prevention (CDC) developed a revised classification scheme in 1993 based on the development of signs and symptoms and the CD4 lymphocyte count (24). The classification was revised again in 1999, allowing HIV-seropositive individuals without other AIDS-defining conditions to be reported (25). This scheme is summarized in Table 47-1. Group A patients are seropositive but essentially symptom free. Group C patients have one or more AIDS-indicator illnesses. A comprehensive list of AIDS-indicator conditions is beyond the scope of this chapter, but suffice it to say that they include most opportunistic infections and malignancies, HIV dementia, and the AIDS wasting syndrome. Group B patients have early symptoms of immune deficiency in the absence of an AIDS-indicator condition. Patients are further subdivided into categories 1, 2, and 3, corresponding to CD4 counts of 500/mm³ or above, 200 to 499, and less than 200, respectively. Patients falling into either group C or category 3 are classified as having AIDS.

Demographics

The World Health Organization (WHO) estimates that as of December, 2007, 30.8 million adults and 5 million children worldwide are living with HIV-1 infection. Half of those infected are women. HIV continues to run rampant in less developed areas of the world, particularly in sub-Saharan Africa and Southeast Asia, in spite of efforts aimed at prevention (26). About 1.3 million people are infected with HIV in North America. In the United States, there are now about 17,000 deaths annually and in 2005, among persons with HIV, 20% were female, 35% white, 44% black, and 19% Hispanic, reflecting the continuation of a significant shift into minority populations (27).

Documented Routes of Transmission

Documented routes of transmission include sexual contact with infected individuals, percutaneous or mucous membrane exposure to infected blood or body fluids, or transplacental, perinatal, or breast milk transmission from mother to infant. In 2005, of 322,000 HIV-positive men in the United States, 59% were exposed through maleto-male sexual transmission, 20% through intravenous drug use, and 11% through high-risk heterosexual sex. Of the 96,000 women, 65% contracted HIV through high-risk heterosexual exposure and 35% through intravenous drug use (27).

Occupational Exposure

The risk of HIV-1 infection is estimated to be 0.3% after percutaneous injury involving infected blood (28) and 0.1% after mucous membrane exposure (29). Universal precautions should be used at all times that contact with blood or body fluids may be anticipated. These include the use of gloves to prevent potential exposure to infectious body fluids or broken skin during procedures such as wound care and electromyography (EMG), and the use of a gown, goggles, and a mask during procedures in which spattering of blood is possible.

Postexposure prophylaxis (PEP) is recommended for percutaneous or mucous membrane exposure to blood or visibly bloody fluid, semen, vaginal secretions, cerebrospinal, synovial, pleural, pericardial, and amniotic fluids. In a case control study, postexposure zidovudine decreased HIV-1 infection by 81% (30). Recently updated guidelines by the New York State Department of Health recommend initiating PEP as soon as possible after it has been determined that an exposure has occurred, ideally within 2 hours and not later than 36 hours. The combination of Combivir with tenofovir is one preferred regimen, but consultation with an HIV specialist is highly recommended in order to choose a regimen based on the source patient’s HIV strain and antiretroviral resistance, if known (31). A national PEP line is maintained by the University of California, San Francisco (http://www.ucsf.edu/hivcntr/PEPline/) 1-888-448-4911. Expert clinicians are available 24 hours a day, to offer advice in the event of an exposure. Nevirapine is not recommended for PEP due to the incidence of severe hepatitis (32). A medical evaluation, counseling, and follow-up by an experienced physician should be provided promptly, but initiation of PEP should not be delayed (33,34) <http://www.hivatis.org/>. Recommendations for pregnant health care workers are similar except that efavirenz and amprenavir should be avoided (35,36).

Prevention of Transmission Among the Disabled

One of the most significant things rehabilitation professionals can do to stop the spread of HIV is to educate their patients as to the modes of transmission and means of preventing transmission. High-risk behaviors must be strongly discouraged, and education in safer sex practices should be included as part of all discussions on sexuality.

The most effective protective measure is the use of a barrier device whenever contact with infectious fluids is anticipated. This includes the use of condoms, the dental dam for oral sex, and the use of gloves or a finger cot for digital anal penetration. Safe touching should be substituted for scratching, biting, and abrading activities that might lead to inadvertent fluid exposures. Water-soluble lubricants should be used particularly in insensate areas to reduce the likelihood of inadvertent abrasion. Mutual masturbation may be suggested as an activity that is virtually risk-free. Patients should be reminded to clean and disinfect all enrichment aids (sex toys) using a solution such as 10% chlorine bleach.

When patients experience direct exposure to infectious fluids, prophylaxis should be offered as it is to health care workers. Because about a fourth of children delivered vaginally to untreated infected mothers will also be infected, prophylaxis should also be used to reduce vertical transmission. A prospective trial showed that pregnant women who took zidovudine could decrease the risk of perinatal transmission by 67% (37,38), and several subsequent trials have shown that the risk of mother-to-child transmission can be reduced substantially by perinatal treatment of both mother and neonate (39,40). Prevention of transmission in the adolescent patient demands particular attention (41). The avoidance of HIV transmission among patients who lack the capacity to modify their behavior, such as brain-injured individuals with impaired impulse control, remains a difficult area without clear-cut solutions (42,43).

CLINICAL EVALUATION OF HIV

Serologic Testing

The mainstay of HIV-1 testing involves screening for anti-HIV-1 antibodies with the ELISA, with the Western blot test used for confirmation. Serologic testing can only detect infection after seroconversion has occurred, which may take up to 3 to 6 months after acute infection. When ELISA screening and confirmatory Western blot testing are used, the false-positive rate is negligible. Pre- and post-test counseling are advisable to educate patients about the need for repeat testing, as well as modification of high-risk behaviors and, in the event of a positive test, the need to seek specialized medical care. Home test kits, in which samples of saliva, blood, or urine can be collected by the patient at home or in a doctor’s office and sent directly to testing laboratories, are available. Recently, the CDC has endorsed routine testing for HIV in medical settings with an opt-out clause. This policy change is hoped to help identify patients with HIV who may otherwise not have sought testing or whose physicians may not have thought were at increased risk (44).

Evaluation of the Seropositive Patient

It is particularly important to identify seropositive individuals both because medical therapy for HIV is highly beneficial and in order to identify the individuals at risk for spreading the infection to others. In patients with unexplained sweats, fevers, or weight loss, skin lesions characteristic of opportunistic infections or malignancy, dyspnea unrelated to intrinsic cardiac or pulmonary disease, or altered neurologic function not attributable to a specific lesion, injury, or toxin, HIV infection must be considered in the differential diagnosis. The presence of other sexually transmitted diseases (STDs) also should be considered an indication for HIV testing. Even the presence of diseases seen at higher rates in HIV patients, such as tuberculosis (TB), should be considered an indication for testing.

The physical exam should focus on findings often seen in association with HIV. The skin and oral cavity should be carefully examined for mucocutaneous lesions, particularly those associated with Kaposi’s sarcoma (KS). Lymphadenopathy and hepatosplenomegaly are also important indicators. Because of the propensity of HIV to involve the nervous system, a detailed neurologic examination is essential. Peripheral neuropathies, cognitive disorders, myelopathy, and focal CNS dysfunction may all be seen in association with HIV. Although cognitive dysfunction is not common prior to the development of AIDS, a neuropsychologic evaluation is helpful to establish a baseline.

The laboratory evaluation should include routine chemistries and a complete blood count. A mild increase in transaminases may be seen, along with an elevated erythrocyte sedimentation rate, anemia, and general cytopenias. Serum protein electrophoresis may demonstrate an increase in immunoglobulins. Lymphocyte evaluation may demonstrate a decrease in CD4-positive lymphocytes or a reversal in the CD4/CD8 ratio. Viral load tests such as the polymerase chain reaction (PCR) or branched deoxyribonucleic acid (DNA) are important for establishing prognosis and for evaluating the effectiveness of antiretroviral treatments.

TREATMENT STRATEGIES IN AIDS

Because clinically latent stages of HIV-1 infection involve rapid viral replication, strategies now aim to decrease steady-state viral RNA levels. The benefits of decreasing HIV viral load must be weighed against side effects and the risk of developing resistant strains (45,46). Published guidelines are meant to be interpreted by specialized providers <http://www.hivatis.org> (47,48). In general, the aim is to start antiretroviral medications before complications related to immunosuppression occur and when the patient can achieve maximum adherence. Medications commonly used in HIV along with some of their indications and side effects are summarized in Table 47-2. Numerous important side effects and drug interactions may occur that may limit effectiveness or tolerability of therapy, or result in dangerous iatrogenic complications and disability (49,50).

TABLE 47.2 Common Drugs Used in HIV

Drug	Common Usage	Side Effects	Drug Interactions
Antiretrovirals (nucleoside analog RT inhibitors)
Zidovudine (AZT)	Used in combination	Nausea, headache, fatigue, anemia, neutropenia, myopathy	Increased hepatotoxicity of amphotericin B, ganciclovir
Didanosine (ddI)	Used in combination	Painful neuropathy, pancreatitis, mitochondrial toxicity, lactic acidosis	May decrease absorption of other drugs
Zalcitabine (ddC)	Rarely used due to toxicity	Painful neuropathy, pancreatitis, oral ulcers, granulocytopenia, rash, fever, hepatitis	Increased toxicity with foscarnet and valproic acid; alcohol may increase risk of pancreatitis
Lamivudine (3TC)	Used in combination	GI intolerance
Emtricitibine (FTC)	Used in combination	GI intolerance
Abacavir	Used in combination	GI intolerance, hypersensitivity reaction may be fatal, Increased risk of MI (308)
Stavudine (d4T)	Rarely used due to toxicity	Painful neuropathy, hepatic dysfunction, mitochondrial toxicity, lactic acidosis
Antiretrovirals (nucleotide analogue RT inhibitors)
Tenofovir	Used in combination	GI side effects
Antiretrovirals (nonnucleoside analogue RT inhibitors)
Efavirenz	Used in combination	Rash, neurologic and sleep disturbances, lipid abnormalities	Many drug interactions, may decrease PI levels
Nevirapine	Used in combination	Rash, hepatitis	May decrease protease inhibitor levels
Delavurdine	Used in combination	Rash	May decrease didanosine levels
Etravirine	Works in NNRTI-resistant virus	Rash
Antiretrovirals (protease inhibitors)
Saquinavir	Used in combination	GI distress, elevated LFTs	Decreased bioavailability of Ca channel blockers
Indinavir	Used in combination	Hepatotoxicity, nephrolithiasis, glucose intolerance	As above, plus increased desipramine, rifabutin, ergotamine, and amiodarone levels; prolonged sedation with midazolam and triazolam; decreased OCP effectiveness; fatal arrhythmias with astemizole
Ritonavir	Used to boost other PI levels	GI upset, perioral paresthesias, alteration of taste, headache, elevated LFTs, lipid abnormalities	Similar to indinavir, but may be more pronounced, failure of oral contraception, multiple P450 interactions—most potent P450 CYP3A inhibitor decreases some drug levels
Nelfinavir	Used in combination	Diarrhea, lipid abnormalities
Amprenavir	Used in combination	GI disturbance
Fos-amprenavir	Prodrug of amprenavir	GI disturbance
Lopinavir/ritonavir	Used in combination	GI disturbance, glucose intolerance, lipid abnormalities	See ritonavir
Atazanavir	Used in combination		Contraindicated with proton pump inhibitors and interacts with H2 blockers.
Tipranavir	Used in combination	Hyperbilirubinemia
Darunavir	Used in combination	Gi disturbance	Multiple, difficult to predict
		GI disturbance
Antiretrovirals (novel agents)
Enfuvirtide	Fusion inhibitor	Injection site reactions
Maraviroc	CCR5 entry inhibitor	Hypotension	Multiple
Raltegravir	Integration inhibitor	Elevated CK
Combination agents (names outside the United States may differ)
Combivir	Zidovudine + lamivudine	Similar to individual components	Similar to individual components
Epzicom	Abacavir + lamivudine	Similar to individual components	Similar to individual components
Trizivir	Zidovudine + lamivudine + abacavir	Similar to individual components	Similar to individual components
Truvada	Tenofovir + emtricitabine	Similar to individual components	Similar to individual components
Atripla	Tenofovir + emtricitabine + efavirenz	Similar to individual components	Similar to individual components
Kaletra	Lopinavir + ritonavir	Similar to individual components	Similar to individual components
Prophylactic agents
Trimethoprim/sulfamethoxaxole	PCP prophylaxis and treatment, toxoplasmosis prophylaxis	Rash, fever, neutropenia, thrombocytopenia, hepatitis, headache, meningitis, hyperkalemia	Potentiation of coumadin, oral hypoglycemics and, phenytoin; decreased effectiveness of cyclosporine
Dapsone	PCP prophylaxis	Rash, fever, hemolysis in G6PD deficiency	ddI decreases absorption; decreased effectiveness of oral contraceptives
Pentamidine	PCP prophylaxis and treatment	Aerosol: bronchospasm; IV: nephritis, pancreatitis, hypo- or hyperglycemia, rash, neutropenia	Renal failure with Amphotericin B; hypocalcaemia with foscarnet
Rifabutin	MAC prophylaxis	GI, auditory, iritis	Decreases levels of guanidine, oral contraceptives, phenytoin, methadone, digoxin, cyclosporine, azoles, corticosteroids, beta blockers
Azithromycin	MAC prophylaxis	GI upset
Common treatments
Acyclovir	Herpes simplex, zoster	Diarrhea, phlebitis (IV)
Ganciclovir	CMV	Neutropenia, GI	Increased nephrotoxicity with cyclosporine
Foscarnet	CMV	Nephrotoxicity, seizure, nausea, hypomagnesemia, calcemia and natremia, nephrotoxicity, headache	Hypocalcemia with pentamidine
Cidofovir	CMV	Nephrotoxicity
Fluconazole	Antifungal: candida and cryptococcus	Hepatotoxicity, nausea, rash	Decreased absorption with cimetidine; decreased levels with carbamazepine and rifampin; increases phenytoin levels
Ketoconazole	Antifungal: candida	GI upset, pruritis, headache, rash	Fatal arrhythmias with terfenadine and astemizole; decreases rifampin; potentiates coumadin
Itraconazole	Antifungal: histoplasmosis, aspergilla	Hepatitis, GI upset, rash headache	Fatal arrhythmias with terfenadine and astemizole; decreased levels with carbamazepine; increased sedation with midazolam
Amphotericin B, Liposomal ampho B	Antifungal: serious fungal infections	Nephrotoxicity, fever, chills, hypomagnesemia, hypocalcemia	Dosage must be adjusted in renal failure
CMV, cytomegalovirus; IV, intravenous; LFT, liver function test; MAC, Mycobacterium avium complex; OCP, oral contraceptic preparation; PCP, Pneumocystis carinii pneumonia.

Antiretroviral Agents

Combination therapy with three or more active antiretroviral agents in order to achieve an undetectable HIV viral load in plasma has become the standard of care. Usual combinations consist of two nucleoside analogue reverse transcriptase (RT) inhibitors plus a protease inhibitor or nonnucleoside analogue RT inhibitor. Other combinations can also be effective; however, numerous clinical trials have demonstrated the emergence of resistant strains with monotherapy and dual therapy (51, 52, 53).

RT Inhibitors

In 1987, the FDA approved zidovudine (AZT), a nucleoside analog RT inhibitor. Subsequently approved were other nucleoside analogs, including didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), emtricitabine (FTC), abacavir, and the nucleotide analogue RT inhibitor, tenofovir (54, 55, 56, 57, 58). These agents act by inhibiting the process of reverse transcription, preventing viral RNA from being transcribed into cellular DNA. Currently, there are four non-nucleoside analogue RT inhibitors approved in the United States. These are efavirenz, nevirapine, delavurdine, and etravirine. As with the nucleoside analogues, they can be highly effective in suppressing the HIV viral load when used in combination with other agents (59, 60, 61, 62, 63).

Protease Inhibitors

As of this writing, ten protease inhibitors have been approved by the FDA for HIV infection: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, fos-amprenavir, lopinavir, atazanavir, tipranavir, and darunavir (57,64, 65, 66, 67, 68). These result in the production of immature, noninfectious HIV-1 particles by blocking the cleavage of HIV-1 polyproteins into component proteins. Combinations of protease inhibitors and RT inhibitors have been shown to reduce plasma HIV-1 RNA levels below detectable levels and to reduce morbidity and mortality. The protease inhibitors are often “boosted” to higher plasma levels by addition of low-dose ritonavir, which is a potent inhibitor of the cytochrome p450 system.

Novel Agents

Currently, there is one fusion inhibitor, enfuvirtide, approved for use by the FDA. This polypeptide binds to GP41 transmembrane protein on the HIV virion and prevents the conformation change required to fuse the virion with the CD4 cell membrane thus inhibiting viral entry. It is injected subcutaneously and thus is most often used in patients who have developed resistance to other agents (69).

In August 2007, the first CCR5 antagonist entry inhibitor was FDA approved in the United States. CCR5 is one of the coreceptors that HIV commonly uses to bind and enter CD4-positive T-cells. Maraviroc acts as a CCR5-binding antagonist that blocks HIV entry into the cell. Since some strains of HIV can use a different co-receptor (CXCR4), a test must first be run to determine if the individual patient’s strain of HIV contains CXCR4 variants, prior to use of CCR5 antagonists (70).

In October 2007, the first integrase inhibitor, raltegravir, was FDA approved for use in the United States. This antiretroviral blocks a step of HIV viral replication after reverse transcription, in which the viral DNA integrates into the host cell genome.

The availability of the new classes along with improved resistance profiles of some of the new agents in older classes of antiretrovirals has recently led to the exciting possibility of controlling viral replication in patients who previously had virus resistant to all available ART.

Immune Stimulants

Cytokines have been used in clinical trials to stimulate production of CD4 cells (71). Interleukin-2 can stimulate CD4 cell production, but it also increases virus production. The use of stimulating cytokines in conjunction with potent antiretroviral combinations is effective but is not often necessary.

COMMON CAUSES OF DEBILITY

Although HIV itself is felt to be responsible for many forms of functional compromise, particularly in the CNS, a large number of disabling syndromes are associated with opportunistic infections and malignancies. The following sections are organized by the types of impairment syndromes that result and, to the extent practical, in order of the timing of their appearance in HIV infection. A summary of these is listed in Table 47-3.

Respiratory Compromise and Disseminated Infection

Pathogenic Fungi

Endemic pathogenic fungi such as histoplasma capsulatum, blastomyces dermatidis, and coccidioides immitis can cause disease in normal hosts and particularly in HIV infection and AIDS. Patients often present with slowly progressive wasting, fevers, weight loss, or ulcerations of skin. Bone marrow dysfunction may occur and, occasionally, disseminated intravascular coagulation and death. The chest x-ray may be normal or show a progressive infiltrate. The serum test for histoplasma polysaccharide is specific and sensitive. Treatment consists of induction with amphotericin B and maintenance with itraconazole (72,73).

Mycobacterium TB

TB caused by mycobacterium TB (mTB) is common and severe, and seen early in the course of AIDS, often at CD4 counts above 200 cells/µL (74,75). Symptoms may be subtle. TB may disseminate to a wide variety of organs including the brain and spine. Guidelines for the diagnosis, treatment, and prophylaxis of infectious TB have been detailed by the CDC and elsewhere (76, 77, 78, 79). Of concern, however, are outbreaks of multi-drug-resistant TB (80,81).

Pneumocystis Jiroveci Pneumonia (PCP)

Pneumocystis jiroveci (formerly Pneumocystis carinii) is a fungus-like pathogen that causes PCP, the most common AIDS-defining illness in the United States, accounting for about 18% of cases (82,83). Seen throughout the course of the disease, symptoms may develop gradually and include dyspnea on exertion, shortness of breath, cough, weight loss, fevers, and night sweats. The chest x-ray may show a diffuse alveolar infiltrate and serum lactate dehydrogenase (LDH) may be elevated. Diagnosis is most often made by identification of Pneumocystis organisms in expectorated sputum or from bronchoscopic specimens.

A room air blood gas with PaO₂ ≤70 mm Hg, indicates severe disease, which is treated with steroids in addition to intravenous trimethoprim/sulfa, primaquin with either clindamycin or dapsone, or intravenous pentamidine. Trimetrexate plus dapsone may also be used. Prophylaxis with trimethoprim/sulfa or dapsone is a mainstay of AIDS treatment when CD4 counts are less than 200.

Mycobacterium Avium Complex

Mycobacterium avium complex (MAC), an atypical mycobacterial infection, is one of the most common opportunistic infections in AIDS patients in the United States, with an incidence of 18% to 43% in untreated patients (84, 85, 86). It may be present as a nonpathogenic colonizer or may cause disease in the bone marrow, lungs, liver, colon and rarely, the CNS. It occurs late in the course of the disease and may be indolent, with fevers, night sweats, weight loss and wasting, cough, diarrhea, abdominal pains, lymphadenopathy, and lymph node pain.

Effective drug combinations for treatment of MAC include clarithromycin, with ethambutol as an alternative. Rifabutin, clofazamine, ethambutol, and ciprofloxacin azithromycin and aminoglycosides (amikacin) have also been used (87). Clarithromycin has been shown to be effective in preventing disseminated MAC (88). Primary prophylaxis against MAC with azithromycin is recommended for those with CD4 counts less than 50 to 75 cells/µL (89).

Gastrointestinal and Swallowing Disorders

Gastrointestinal disease in AIDS is common and presents with diarrhea, weight loss, biliary disorders, abdominal pain, dysphagia, and oral disease (90, 91, 92, 93). A wide range of causes including cytomegalovirus (CMV), herpes simplex virus (HSV), MAC, intestinal parasites, and malignancies such as KS and non-Hodgkin’s lymphoma are seen. Drug reactions are also a frequent cause. Dysphagia is most often caused by Candida albicans, HSV, or CMV esophagitis. Other causes include hairy leukoplakia, KS, human papilloma virus infection, and neurogenic causes. The Sicca syndrome, seen often in association with lymphadenopathy, may be treated symptomatically with increased fluids, artificial tears, and careful attention to oral hygiene. Colitis often presents with abdominal pain and bloody or mucous diarrhea and is most often caused by CMV, which responds to treatment with ganciclovir (94). Clostridium difficile, Campylobacter jejuni, Entamoeba histolytica, and Shigella flexneri are also seen in colitis in AIDS patients.

HIV-Related Liver Disease

Over the past several years, liver disease has risen to prominence in HIV patients. Many ARTs are hepatotoxic and a high percentage of HIV patients are also infected with hepatitis B, C, or both. Moreover, a higher percentage of HIV patients develop chronic infections that may progress more rapidly to cirrhosis than would otherwise be expected. Treatment for hepatitis C with pegylated interferon and ribavirin is commonly used in HIV patients and hepatitis B can be treated with the RT inhibitors lamivudine or emtricitabine, and tenofovir (79,95, 96, 97, 98, 99, 100).

Candidiasis

Oral candidiasis (thrush) occurs in 43% to 93% of AIDS patients (101). It most often appears as creamy white, yellow or erythematous patches on the palate, tongue, and buccal mucosa and causes angular cheilitis and fissures at the corners of the mouth. With more severe immunodeficiency, candida may extend into the pharynx and esophagus. It presents more often in patients with CD4 counts less than 200 cells/µL, but can occur at higher counts as well. Candidiasis may be treated with oral nystatin suspension, clotrimazole troche, fluconazole or other azoles, or echinocandins.

Kaposi’s Sarcoma

KS is a highly vascular malignant lesion containing endothelial cells and spindle-shaped mesenchymal cells and is associated with HHV8 coinfection. It can involve skin, oral mucosa, and visceral organs and often appears as dark blue or purple papules or nodules. Cosmetically, lesions can be treated by laser bleaching and spot radiation. Often, KS will regress with immune reconstitution on ART (102). More severe disease has been treated with antiretrovirals and drugs such as foscarnet (103), localized radiation, immunotherapy with interferon alpha, cytotoxic chemotherapy, and liposomal doxorubicin (104,105). Intralesional human chorionic gonadotropin (hCG) has also been effective (106). Associated edema may be controlled with the use of compressive garments, and painful lesions in the feet may be managed with the use of soft insoles and by unweighting the affected extremity.

Intestinal Parasites

Cryptosporidium parvum is an intracellular protozoan usually seen with CD4 counts below 200. It is responsible for about 1% of AIDS deaths (107). Oral paromomycin or azithromycin may be effective in decreasing diarrhea and stabilizing body weight (108). Microsporidiosis causes similar symptoms and may be treated with albendazole (109). Other intestinal parasites include isospora belli, E. histolytica, and giardia lamblia (110,111).

TABLE 47.3 Common Functional Impairment Syndromes in HIV

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Cause of Impairment	When Seen	Features	Prognosis	Management
Respiratory compromise and disseminated infection
Pathogenic fungi	Pre-AIDS and AIDS	Wasting, fevers, etc.	Benign or fulminate	Antifungal agents
mTB	Early AIDS	Nonspecific fever, cough, etc.	Fair, good with ART	Antituberculin therapy
PCP	Throughout AIDS	Nonspecific fever, cough, etc.	Good except in late AIDS	TMPX, dapsone, pentamidine; prophylaxis in all AIDS
MAC	Late AIDS	Fever, night sweats, weight loss, etc.	Poor but better with ART	Clarithromycin, ethambutol etc; combination therapy. prophylaxis when CD4 count is <50-75
GI and swallowing disorders
Neurogenic swallowing disorders	Throughout AIDS, especially late	Related to underlying neurologic disorder	Related to underlying disorder	Video fluoroscopy, modified swallow, parenteral nutrition
Sicca syndrome		Impaired lacrimation and salivation	Benign course	Symptomatic treatment (artificial tears, oral lubricants, etc.)
Candidiasis	Pre-AIDS and AIDS	Oral plaques, dysphagia	Good with treatment	Topical antifungal agents; systemic agents in severe cases
Kaposi’s sarcoma	Throughout AIDS	Characteristic lesions	Slow progression	Appropriate chemotherapy
Intestinal parasites	Late AIDS	Diarrhea	Good if diagnosed	Antiparasitic agents
Weakness and fatigue
Chronic fatigue	Pre-AIDS and AIDS	Many causes	Fair	Energy conservation and pacing
Fibromyalgia	Any stage of HIV	Pain and fatigue	Good	Standard measures (NSAIDS, etc.)
Myopathy (polymyositis)	Any stage of HIV	Proximal weakness	Good	Steroids, exercise as tolerated
AIDS wasting syndrome	Late AIDS	Proximal weakness	Poor	Supportive care, anabolic steroids, human growth hormone
Pain syndromes and neuropathies
Arthritis and arthralgias		Psoriasis associated, Reiter’s syndrome, reactive and HIV	Similar to idiopathic varieties	Similar to idiopathic varieties (NSAIDS, injections, joint preservation, etc.)
Distal symmetric neuropathy	Increased with decreased CD4 count	Distal numbness, pain, and decreased strength	Responds to symptomatic therapy	Tricyclics, neuroleptics, heat/cold, gait aids, orthotics
Segmental neuropathies	Early or late	Zoster, mononeuritis simplex/multiplex, vasculitis, etc.	Variable	Similar to that in non-HIV patients
Drug-induced neuropathies, vitamin deficiencies	Related to drugs	Didanosine, zalcitabine, stavudine, vincristine, dapsone, rifampin, isoniazide, ethambutol	Good	Cessation or alterations of medications, vitamin supplementation, symptomatic management
Plantar KS	Throughout AIDS	Characteristic lesions	Good	Radiation, custom insoles, etc.
Cognitive dysfunction
HIV dementia	Late AIDS, but occasionally seen at presentation	Decreased memory, dysphagia, associated myelopathy	Poor	Antiretrovirals, memory book, adaptive strategies, decreased stimulation, etc.
Cryptococcal meningitis	Throughout AIDS	Fever, headache, meningismis, etc.	About 50% respond to treatment	Amphotericin B, followed by lifetime fluconazole
Neurosyphilis	Throughout AIDS	Nonspecific CNS	Fair, frequent relapse	High-dose PCN
Encephalitis (herpesviruses)	Throughout AIDS	Headache, seizure, altered consciousness, focal signs	May be self-limited, fair to good with antiviral treatment	Acyclovir for HSV, ganciclovir or foscarnet for CMV
Focal lesions (see below)	Throughout AIDS	Focal signs	Lesion specific	See below
Metabolic/iatrogenic dementia	Throughout HIV	Nonspecific CNS	Good	Proper diagnosis and correction of underlying problem
Focal brain disorders
Cerebral toxoplasmosis	Throughout AIDS	Focal signs, altered consciousness, ring-enhancing lesions	Good with treatment	Pyrimethamine and folinic acid, plus sulfadiazine or clindamycin; prophylaxis when CD4 count is ≤100
PML	Advanced AIDS	Focal signs, altered consciousness	Very poor except in rare cases	Antiretrovirals
Primary CNS lymphoma	Advanced AIDS	Similar to above, occasional paraneoplastic signs	Extremely poor	Palliative radiation extends both quality and quantity of life
Other metastatic disease	Throughout AIDS	Similar to above	Lesion specific	Appropriate to lesion
CNS abscesses	Throughout AIDS	Similar to above	Lesion specific	Drainage of abscess, antimicrobials, antituberculin agents
CMV retinitis	Advanced AIDS	Visual field loss	Progressive	Ganciclovir and foscarnet
Radiculopathies and myelopathies
Inflammatory demyelinating polyneuropathies	Early in HIV	Guillain-Barré, CIDP may be associated with nucleoside analogues	Very good	Same as in idiopathic forms
CMV polyradiculopathy	Late AIDS	Flaccid paralysis

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