Darius A. Rastegar
Michael I. Fingerhood
In the decades since the onset of the human immunodeficiency virus (HIV) epidemic, the prognosis for patients in the United States has greatly improved (1). Highly active antiretroviral treatment (HAART) and prophylaxis for opportunistic infections have significantly lowered the mortality from acquired immunodeficiency syndrome (AIDS) and have improved the lives of many. These changes have made the care of HIV-infected patient more rewarding yet more complex.
The role of primary care practitioners in caring for HIV-infected individuals is controversial. Some studies have found poorer patient survival and lower adherence with guidelines among physicians who care for small numbers of patients. However, it appears that the care provided by experienced generalists is comparable to that provided by specialists (2). Most would agree that ongoing experience with the care of HIV-infected patients is important and that a physician with only a few HIV-infected patients should consider referring these patients to an expert.
Primary care practitioners certainly do play an important role in identifying those who are infected and counseling those at risk of becoming infected. This chapter reviews the issues involved in the ambulatory care of HIV-infected patients. It does cover all of the details of antiretroviral therapy and HIV-related complications; other resources for obtaining more extensive and updated information are listed athttp://www.hopkinsbayview.org/PAMreferences.
General Considerations
Causes
HIV is a member of the lentivirus subfamily of human retroviruses and was found to be the etiologic agent of AIDS
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in 1983. These viruses code for an enzyme known as reverse transcriptase, which permits transcription of viral ribonucleic acid (RNA) into proviral deoxyribonucleic acid (DNA) and subsequent integration into the host's cellular genome, leading to a persistent and latent infection. The retroviruses are associated with diseases of long incubation period, involvement with the hematopoietic and central nervous systems, and immune suppression. Other related human retroviruses include HIV-2 and the human T-cell lymphotropic viruses (HTLV-I, and HTLV-II). HIV-2, found primarily in West Africa, has also been associated with AIDS but has a more prolonged incubation period (3). HTLV-1 has been associated with tropical spastic paraparesis and T-cell leukemia/lymphoma, and HTLV-II has not yet been associated definitively with any human disease (4).
Epidemiology
The Centers for Disease Control and Prevention (CDC) estimates that over 1 million Americans are infected with HIV, and 25% of them do not know that they are infected. (5) Worldwide, over 39 million people are HIV infected (6). Most HIV infections occur in adults who belong to the major risk groups for HIV transmission: men who have sex with men (MSM), heterosexual partners of infected persons, injection drug users, and infants of infected women.
Transmission and Prevention of Transmission
Primary care practitioners play an important role in counseling patients at risk of acquiring HIV. However, doing so requires actually evaluating a patient's risk of infection. This involves questions about an individual's sexual practices and drug use; topics that physicians (and patients) are often uncomfortable discussing (7). Primary care practitioners should ask all their patients about their sexual practices, as well as drug and alcohol use, in an open and nonjudgmental fashion, and educate them about the risks they may be taking. Table 39.1provides estimates of transmission risk associated with different exposures.
HIV-1 occurs in highest concentrations in blood and semen. It also occurs in lower concentrations in cervical and vaginal secretions, saliva, tears, breast milk, and amniotic fluid. HIV transmission is most commonly through blood and semen, but vaginal secretions and breast milk also have been implicated in the transmission process.
Sexual Transmission
HIV infection can be transmitted during sexual intercourse between men and between men and women. The risk of transmission varies depending on a number of factors, including the type of sexual practice, the HIV viral RNA level of the infected person, and likely other factors (yet to be determined) in the immune system of the uninfected person.
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TABLE 39.1 Estimated Per-Act Risk of Acquiring HIV, by Exposure* |
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The following patterns, practices, and situations carry the greatest risk of infection:
The prevention of sexual transmission of HIV requires that sexually active people choose sexual practices that eliminate the high-risk situations listed above, as well as other lower risk practices, including oral–genital contact. In the care of every patient who is sexually active and in public education messages, the fundamentals of safe, possibly safe, and definitely unsafe sex should be clearly communicated (Table 39.2). Specific instructions for the most effective use of condoms (Table 39.3) are particularly important. Postexposure prophylaxis with antiretroviral medication after sexual contact with someone who is infected (similar to postoccupational exposure prophylaxis; seeOccupational Exposure, below) may be considered in certain situations (8).
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TABLE 39.2 Safe Sex Guidelines |
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The risk of sexual transmission also varies depending on the serum level of HIV RNA (“viral load”) in the infected person. In a study of 415 HIV infection-discordant heterosexual couples in Uganda, researchers reported an average transmission rate of approximately 12 per 100 person-years. However, there were no instances of transmission when the infected partner's HIV RNA level was below 1,500 (9).
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TABLE 39.3 Instructions for Condom Users |
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Transmission through Transfusion of Blood and Blood Products
HIV can be transmitted only by whole blood, blood cellular components, plasma, and clotting factors. No other blood products (e.g., immune globulin preparations, albumin, plasma protein fraction, hepatitis B vaccine) have been implicated.
The risk of acquiring HIV through a blood transfusion is now infinitesimally small. The estimated risk of HIV infection is 1:153,000 per unit of blood transfused (10). This low risk has been achieved by blood donor education programs (to eliminate donors who belong to high-risk groups), uniform blood product screening since April 1985, HIV-inactivating treatment of clotting factor concentrates, the use of autologous blood transfusions for elective surgery, and efforts to avoid nonessential transfusions.
Needle Transmission
Sharing of needles by injection drug users accounts for a large proportion of patients with AIDS in the United States. HIV-infected patients in this group pose a threat to both needle partners and sexual partners. In developing countries, this mode of transmission may also occur because of reuse of improperly cleaned needles and syringes for the injections of medicines.
Definitive interruption of transmission by injection drug use requires that the user discontinue the practice as part of a recovery program (see Chapter 29). The interruption of transmission by those who continue injection drug use requires that they avoid needle-sharing. Therefore, drug treatment can serve the dual purpose of treating addiction and preventing HIV transmission. Syringe and needle exchange programs have been shown to decrease needle sharing and to decrease spread of HIV infection. Some have advocated that physicians prescribe clean needles to injection drug users who would otherwise not have access to them to prevent transmission of HIV and other blood-borne diseases. Cleaning needles with bleach before reuse (if done properly) may also reduce the risk of transmission (11).
Perinatal Transmission
Although several routes may account for perinatal transmission from an HIV-infected woman to her infant, most infants acquire their infection at or near the time of delivery because of inoculation or ingestion of maternal blood. Intrauterine transmission by cord blood is less common. Transmission also can occur postnatally through breast-feeding. It is estimated that 7% to 39% of infants born to
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HIV-infected mothers become infected, with the highest rates occurring in infants born to mothers with high viral loads, late-stage disease, early fetal membrane rupture, and placental inflammation.
Prevention of perinatal transmission requires primary prevention through safer sex practices and secondary prevention through HIV testing and subsequent counseling of HIV-infected women about the risks of pregnancy. Antiretroviral therapy with zidovudine or nevirapine has been shown to reduce transmission of HIV to the fetus. However, the current standard of care in the United States is to treat pregnant women who have an HIV RNA level over 1,000 copies per milliliter with a three-drug regimen with the goal of lowering the HIV RNA level to an undetectable level (12). It has been shown that transmission to the infant is rare if the HIV RNA level is below 500 copies per milliliter at the time of delivery. Additionally, elective cesarean section appears to reduce the risk of transmission but is probably of benefit only if the mother does not receive or respond to antiretroviral treatment or does not achieve on HIV RNA level below 1,000 on therapy.
Casual Contact and the Risk of Human Immunodeficiency Virus Transmission
Casual transmission of HIV does not occur. Thus, household contacts of HIV-infected patients who are not sexual partners are not at risk during ordinary circumstances. Although the virus has been isolated in urine and saliva, there have been no documented cases of transmission through kissing or through exposure to urine, stool, or saliva. Nevertheless, it is generally recommended that the same precautions taken to prevent transmission of hepatitis B in the household setting should be observed by HIV-infected people (see Chapter 47).
Occupational Exposure
Health care workers have an extremely low but finite risk of occupational infection with HIV. The predominant occupational risk is through accidental needlestick exposure. Most cases of HIV transmission by needlestick have occurred via a large-bore needle. Accidental infection is preventable by conscientious use of universal precautions (Table 39.4). “Universal” refers to the fact that these precautions should be followed in the direct care and in the handling of the body fluids of all patients (not just those known to be infected with HIV).
If a health care worker has a percutaneous injury (needlestick or cut) or contact of mucous membrane (eye or mouth) or nonintact skin with blood, tissues, or other body fluids, the source patient should be assessed clinically and, tested for HIV infection (if consent is obtained). As soon as possible after exposure, the exposed worker should also be counseled and, if consent is obtained, tested for HIV infection. If the source patient is HIV negative and has no clinical indicators of or risk factors for HIV infection, no further followup of the exposed worker is necessary. The U.S. Public Health Service recommends postexposure prophylaxis with antiretroviral medications for occupational exposures to HIV in certain situations depending on type of exposure and exposure source; these guidelines can be accessed at the AIDSinfo website (http://www.AIDSinfo.nih.gov) (13). Postexposure prophylaxis should be initiated within 1 to 2 hours after exposure. The optimal duration of therapy is unknown, but 4 weeks is suggested. Most health care institutions have postexposure protocols and resources for their employees; another resource is the National Clinicians’ Postexposure Prophylaxis Hotline run by staff at the University of California-San Francisco and San Francisco General Hospital (phone: 888-448-4911; http://www.ucsf.edu/hivcntr).
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TABLE 39.4 Health Care Workers' Universal Precautions that Should Be Used in the Care of All Patients |
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Serologic Diagnosis and Counseling
Indications for Serologic Testing
Primary care practitioners are the front line of identifying patients infected with HIV and at risk of acquiring the infection. HIV testing and counseling are indicated both to prevent further transmission of disease and to allow people already infected to be identified so that they can seek appropriate medical care. This is especially important now that potent drugs are available to halt the progression of HIV and prevent infection in newborns.
According to the CDC, voluntary testing should be offered to all patients who have sexually transmitted diseases (STDs), are current or former injection drug users, are hemophiliacs, have active tuberculosis (TB), have received blood transfusions or blood products between 1978 and 1985, are prostitutes, are from developing countries with high rates of HIV infection, have regular sexual partners
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with risk factors or known to be HIV infected, have signs or symptoms suggestive of HIV infection, consider themselves at risk for HIV infection or request testing, or are exposed to blood or other at-risk body fluids (including health care workers who perform invasive procedures); all pregnant women should also be offered voluntary testing. There is a growing list of conditions associated with HIV infection that should also provoke consideration of HIV testing; Table 39.5 lists some of these. There are many HIV-infected persons who do not know that they are infected and who may not have known risk factors; therefore, some have proposed that all adults be tested and have argued that universal testing (every 3 to 5 years) would be cost effective (14).
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TABLE 39.5 Factors That Should Trigger Consideration of Testing for Human Immunodeficiency Virus |
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TABLE 39.6 HIV Pretest and Posttest Counseling: Points for Discussion |
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Pretest and Posttest Counseling
The most important aspect of HIV testing is pretest and posttest counseling. Because of the ominous meaning of HIV infection, it is important to ensure privacy and to allow sufficient time to respond to the patient's feelings and questions. Many settings require the patient's written informed consent as part of pretest counseling. Table 39.6 shows recommended points of discussion during counseling. Information about behaviors associated with the risk of acquiring HIV infection is important in both stages of counseling.
Information about available printed materials useful in posttest counseling and about regional programs for HIV-infected patients can be obtained by contacting the CDC National Prevention Information Network
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(http://www.cdcnpin.org; P.O. Box 6003, Rockville, MD 20850; 1-800-458-5231).
Serologic Tests
Antibody to HIV usually appears 6 to 12 weeks after infection but may take as long as 6 months to appear. However, the immune response to HIV does not lead to elimination of the virus from host tissues. A persistent carrier (and persistent seropositive) state follows infection with this type of virus. The diagnosis of HIV infection is based on detection of anti-HIV antibodies by the enzyme-linked immunosorbent assay (ELISA), confirmed by the more specific Western blot (WB) method. In the WB method, several individual HIV proteins are transferred onto nitrocellulose paper and reacted against the patient's serum and known positive and negative sera; HIV antibody is detected by an antihuman immunoglobulin antibody coated with an enzyme that, in the presence of substrate, produces a colored band. A positive WB test (the presence of two of three colored bands representing p24, gp41, and gp120 or gp160) indicates that the patient has been infected with HIV (15).
ELISA tests are reported as positive or negative. WB tests are reported as positive, negative, or indeterminate. The routine processing of a specimen that is positive on initial ELISA testing always includes rerun of the ELISA, to confirm the result, followed by the WB test. The currently used ELISA tests have a sensitivity greater than 99% and a specificity of 99.5%. False-positive ELISA tests (ELISA-positive, WB-negative) may occur when nonspecific serologic reactions are present in patients who have other types of immunologic abnormalities or who have had multiple transfusions or multiple pregnancies. False-positives generally occur in patients from groups at low risk of acquiring HIV infection. False-negative ELISA results may occur in recently infected patients who have not yet made an antibody response.
Patients whose WB tests are reported as indeterminate are those whose sera yield only one of the necessary positive color bands. In most cases, the person is not infected with HIV, especially if the person is at low risk. However, this result may signify that a person is recently infected and will eventually convert to WB-positive. For this reason, the patient should be tested again; if the result remains indeterminate, testing should be repeated in 3 to 6 months. If the WB pattern remains indeterminate for 6 months—in the absence of any known risk factors or clinical findings to suggest HIV infection—the test may be considered negative. Patients who have risk factors or findings compatible with HIV-induced disease should have continued evaluation.
The Food and Drug Administration (FDA) also has licensed a home HIV test kit (Home Access Express, Home Access Health Corporation). This system requires the purchaser to pierce his or her skin with the lancet supplied in the kit, place a few drops of blood on a filter paper test card, and then send the sample to a central laboratory. Routine testing with ELISA and, if necessary, WB is then performed. Sensitivity and specificity for this system is reported to be comparable with routine testing on serum. Counseling is provided over the telephone. There are a number of other home testing kits advertised on the Internet that have not been licensed by the FDA and therefore cannot be recommended for use.
In 2004, the FDA approved the first oral rapid HIV antibody test (OraQuick Rapid HIV-1 Antibody Test, Abbott Diagnostics). Individuals have a test device swabbed around the upper and lower outer gums; this is then inserted in a vial containing a developer solution. After 20 minutes, if HIV antibody is present, two purple lines appear. Although the test is over 99% sensitive and specific, it is still recommended that positive tests be confirmed with a blood test.
HIV RNA level (“viral load”) should not be used for screening purposes, except when acute HIV infection is suspected. The sensitivity and specificity of this test for diagnosing chronic infection is poorer than the ELISA and WB tests; some chronically infected patients have undetectable viral loads, and false-positive viral loads can also occur (16).
Pathogenesis and Natural History
Pathogenesis of Disease in Human Immunodeficiency Virus-Infected Patients
HIV causes illness by impairing important components of the patient's immune system, making the patient susceptible to a wide variety of infections. This virus also causes illness by its direct effect on other body systems, especially the nervous system (17).
HIV preferentially infects human T lymphocytes of the helper/inducer subset (also called CD4 cells), resulting in both quantitative and qualitative defects in helper cell function. Because helper T lymphocytes are crucial in cell-mediated immunity, HIV infection impairs this type of immunity, making the patient susceptible to a number of opportunistic infections. Uninfected people usually have more than 800 CD4 cells per cubic millimeter of blood, whereas HIV-infected patients with opportunistic infections usually have less than 200 CD4 cells per cubic millimeter. Thus, monitoring the CD4 cell count has become useful for predicting the degree of suppression of a patient's cell-mediated immunity, guiding the differential diagnosis of new symptoms, and deciding when to initiate antiretroviral treatment and prophylaxis for opportunistic infection (see Prevention of First Episodes of Opportunistic Infections and Antiretroviral Treatment).
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FIGURE 39.1. Natural history of HIV infection, based on CD4 counts and viral load. (From Fauci AS, Pantaleo G, Stanley S, et al. Immunopathogenic mechanisms of HIV infection. Ann Intern Med 1996;124:654 , with permission.) |
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Other abnormalities of immune function are also found in HIV-infected people. HIV can infect and impair the function of macrophages and monocytes and CD4 lymphocytes. HIV infection may also result in B-lymphocyte activation and nonspecific hypergammaglobulinemia, which may impair the de novo antibody response to some antigens; this may place the patient at increased risk for infection with encapsulated bacteria. Additionally, some studies suggest that HIV infection may cause derangements in polymorphonuclear neutrophil phagocytosis and intracellular killing.
Although most of the illnesses in patients with HIV infection are caused by impaired resistance to infection, a number of clinical manifestations are direct consequences of HIV infection or the immune response to HIV infection. There is good evidence that the virus plays an etiologic role in some neurologic syndromes. Additionally, the virus, or in some cases the immune response to the virus, may cause disease in the gastrointestinal (GI) tract, heart, lungs, and kidneys.
Natural History and Prognosis in Human Immunodeficiency Virus Infection
The mean length of time from seroconversion to symptomatic AIDS in untreated patients is 10 years. The time from infection to symptoms, however, varies considerably from person to person and probably reflects variations in individuals’ immune systems and the virulence of different strains of the virus. Expanded use of antiretroviral therapy, prophylaxis against opportunistic infections, and treatment of AIDS-associated conditions result in delayed progression and longer life expectancies for HIV-infected people. Figure 39.1 shows an overview of the natural history of HIV infection, based on CD4 counts and viral load. Because HIV may remain clinically silent with no demonstrable signs of immunodeficiency or symptoms for many years, asymptomatic patients play a major role in transmitting the virus.
Primary Human Immunodeficiency Virus Infection
Primary HIV infection (“acute retroviral syndrome”) is usually symptomatic in the form of a mild to severe flulike illness. The most common signs and symptoms are fever, lymphadenopathy, pharyngitis, and rash (Table 39.7). The syndrome is nonspecific and cannot be differentiated from other acute viral illnesses on the basis of signs or symptoms alone. Patients often do not seek medical attention and even when they do, HIV infection is generally not recognized. There is a wide range of less common presentations of primary HIV infection that have been reported; these include opportunistic infections, acute renal failure, rhabdomyolysis, and vasculitis.
The incubation period (time from exposure to onset of illness) for the acute syndrome may range from 5 days to
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3 months, but is usually 2 to 4 weeks. During the period of initial infection, blood virus levels are high, HIV is widely disseminated, and there is a transient decrease in circulating CD4 cells. There is an immune response to HIV between 1 week and 3 months after infection, and antibodies are usually detectable 6 to 24 weeks after the initial exposure. The early immune response is associated with a dramatic decrease in viremia, but viral replication is never completely curtailed, particularly in lymphoid tissue.
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TABLE 39.7 Manifestations of Primary Human Immunodeficiency Virus Infection |
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Because of the nonspecific nature of the illness, primary care practitioners need to maintain a high index of suspicion to identify patients with primary HIV infection. The diagnosis can be made by measuring HIV RNA level (viral load) or HIV p24 antigen; an elevated viral load (usually over 100,000 copies per milliliter) or detectable p24 antigen, in the presence of a negative HIV ELISA, establishes the diagnosis. Viral load is a more sensitive test (100%) than the p24 antigen (89%) but is less specific (97% vs. 100% for p24 antigen); however, specificity for viral load approaches 100% if a cutoff of 10,000 copies per milliliter is used (since false-positive viral load titers are usually below this level) (16). Recognizing primary HIV infection is important because it can help prevent further transmission and gives the opportunity to test for transmission of resistant virus (see Drug Resistance section and Antiretroviral Treatment).
Prognostic Indicators
The marker of disease progression that is most familiar to clinicians and has served the test of time is the CD4 lymphocyte count. The absolute number and percentage of CD4 lymphocytes gives the clinician an indication of the degree of immunosuppression and hence can be used to determine to what complications the patient is susceptible. The absolute number of CD4 cells is subject to more variability than the percentage because of normal biologic fluctuations in total lymphocyte counts. Within a year of seroconversion, CD4 cell counts usually drop 200 to 300 per cubic millimeter from the normal range of 800 to 1,200. This decline is followed by an increase to near baseline and then a slow decline of less than 100 cells per year (Fig. 39.1). People with CD4 cell counts greater than 500 are usually asymptomatic and have virtually no risk of developing an AIDS-indicator condition, except for TB, cervical cancer, recurrent bacterial pneumonias, or superficial Kaposi sarcoma (KS), within 18 months. In contrast, those with CD4 cell counts of 100 or less are often symptomatic and have a 60% chance of developing an AIDS-indicator disease (excluding TB, cervical cancer, and recurrent bacterial pneumonias) within 18 months.
A second prognostic indicator of disease progression is HIV viral load (measured as circulating HIV RNA). Among patients with equivalent CD4 lymphocyte counts, patients with higher viral loads on average have a more rapid fall in CD4 counts and clinical disease progression (18). Viral loads are an important way to monitor the effectiveness of antiretroviral therapy; a change in viral load usually occurs before a change in CD4 lymphocyte count, so changes in therapy can be made sooner if viral load is used. Nevertheless, changes in viral load should be interpreted with caution because there is wide intrapatient variation and serial changes are significant only when they are greater than 50% (0.3 log). Viral load varies from undetectable, which is currently less than 400 copies/mL (50 copies per milliliter on ultrasensitive assays), to greater than 1 million copies per milliliter. Immediately after infection, plasma viral load begins to rise and peaks at greater than 100,000 copies per milliliter. It then declines and plateaus in about 150 days to a steady state called the viral set point. The viral set point remains constant for months to years and is a good indicator of risk for disease progression. Viral load again rises just before the development of opportunistic diseases and reaches its highest value with end-stage disease.
Guidelines for the use of CD4 count and viral load in clinical decision-making are found below (see the section on antiretroviral therapy).
Classification System for Human Immunodeficiency Virus Infection and Case Definition for Acquired Immunodeficiency Syndrome
Since 1993, the CDC has used a revised HIV classification system that emphasizes the importance of the CD4 count. Patients are now classified according to three categories of CD4 cell counts:
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They are also classified according to three clinical categories:
Once a person meets criteria for symptomatic HIV or AIDS, that person remains in the same category or advances to a more advanced stage despite interventions that may eliminate symptoms or increase CD4 cell counts. Patients in categories 3 or C meet the case definition of AIDS.
Symptomatic disease in category B includes any condition attributable to immunodeficiency from HIV infection or complicated by HIV infection (except those in categories A and C). Examples of these conditions include bacillary angiomatosis; oropharyngeal candidiasis; vulvovaginal candidiasis that is persistent, frequent, or poorly responsive to therapy; cervical dysplasia (moderate or severe) or cervical carcinoma in situ; constitutional symptoms such as fever (38.5°C [101.3°F] or higher) or diarrhea lasting more than 1 month; oral hairy leukoplakia; herpes zoster of more than one dermatome or recurring at least once; idiopathic thrombocytopenic purpura; listeriosis; pelvic inflammatory disease; and peripheral neuropathy.
The CDC has also expanded the list of AIDS-indicator conditions (Table 39.8). In addition to the 23 clinical conditions originally used to define AIDS, pulmonary TB, recurrent pneumonia (at least two episodes per year), and invasive cervical cancer are now AIDS-indicator diseases.
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TABLE 39.8 AIDS-Indicator Conditions in HIV-Infected Persons |
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Initial Evaluation and Treatment of Human Immunodeficiency Virus-Infected Patients
Baseline History, Physical Examination, and Laboratory Studies
The apparently asymptomatic patient with HIV infection requires an initial evaluation and ongoing psychosocial support and medical assessment. This section describes important manifestations to be sought in initial and subsequent evaluations of HIV-positive patients and prophylactic guidelines, as established by the U.S. Public Health Service in collaboration with the Infectious Diseases Society of America (19). Descriptions of symptomatic manifestations are found under Symptomatic Human Immunodeficiency Virus-Infected Patient, below.
In addition to the HIV-oriented review of systems summarized in Table 39.9, seropositive patients should be asked about a history of STDs, TB, or a positive purified protein derivative (PPD) test; exposure to or history of hepatitis B; immunosuppressive therapy (e.g., an asthmatic patient who intermittently requires corticosteroids); and previous immunizations, including pneumococcal and hepatitis B vaccines. Important information to obtain in the social history includes current sexual practices (type and number of sexual partners), types of contraception used, and past or present injection drug use.
The baseline physical examination should include all organ systems, with special emphasis on the oral cavity, skin,
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lymph nodes, and, in women, the reproductive system. Physical manifestations in these organ systems are particularly important because diseases may be found that are potentially treatable (e.g., seborrheic dermatitis) or that carry prognostic significance (e.g., oral candidiasis).
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TABLE 39.9 HIV-Oriented Review of Symptoms |
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The baseline laboratory evaluation should establish a database that will be useful for identifying already present abnormalities and for comparison when abnormalities are identified at a later time in the care of the patient. This database should include a complete blood count (including a differential and platelet count), hepatitis B surface antigen and antibody, syphilis serology, Toxoplasma antibody, HIV viral load, and CD4 lymphocyte count. Injection drug users and their partners should be tested for hepatitis C antibody. Baseline serologic tests for antibody to cytomegalovirus (CMV) are not generally useful because of the high prevalence of positive tests in the normal population. Unless the patient has a history of a positive PPD skin test or TB, the patient should have a PPD. A chest radiograph should be performed in all patients who have a positive PPD (5 mm or more induration) or have respiratory symptoms or a history of respiratory disease. Table 39.10 gives suggested guidelines for periodic monitoring.
Many patients who complain of no symptoms at baseline will have one or more abnormalities found on physical examination or laboratory evaluation, most commonly generalized lymphadenopathy (see Constitutional Manifestations and Lymphadenophy section), reduced CD4 count, elevated HIV viral load, or mild suppression of the elements of the bone marrow. If a history of constitutional symptoms (weight loss, fevers, night sweats) is elicited, this should be evaluated further, as discussed in the next section. Findings in the oral cavity that may not cause symptoms but suggest some degree of immunodeficiency include oral hairy leukoplakia or early Candida infection (see Oral Lesionssection). A finding of an isolated low platelet count may be indicative of immune thrombocytopenic purpura. Laboratory abnormalities (e.g., anemia) should be evaluated in the same manner as in a non–HIV-infected patient.
Health Maintenance: Monitoring Schedules, Immunizations, and Opportunistic Infection Prophylaxis
Table 39.10 outlines the recommended monitoring schedule for HIV-infected patients according to CD4 cell count. Table 39.11 and this section address immunizations and opportunistic infection prophylaxis to prevent first episodes of preventable diseases. Later sections address the treatment of opportunistic infections (see Symptomatic Human Immunodeficiency Virus-Infected Patient) and the schedule for viral load monitoring and the initiation and long-term use of antiretroviral drugs (Antiretroviral Treatment).
Prevention of First Episodes of Opportunistic Infections
Preventive care for HIV-infected patients should include various vaccinations (Table 39.11). Pneumococcal pneumonia is the leading cause of bacterial pneumonia in HIV-infected patients; pneumococcal vaccine is
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recommended for all HIV-infected patients. It should be given early in the course of HIV infection or, if given in later-stage disease, after the patient has responded to antiretroviral therapy. The evidence for the efficacy of the pneumococcal vaccine is mixed: A randomized controlled trial in Uganda unexpectedly showed a trend toward increased pneumococcal disease among vaccine recipients (20), whereas an analysis of a U.S. database of HIV-infected patients suggested a benefit for those with CD4 counts over 500 (21). The influenza vaccine has been shown to be effective and safe in HIV-infected adults; however, the intranasal influenza vaccine (FluMist) should not be given to HIV-infected individuals, since it contains attenuated virus (22).
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TABLE 39.10 Health Maintenance in the HIV-Infected Patient: Monitoring Timing and Frequency Based on CD4 Count |
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TABLE 39.11 Health Maintenance in HIV-infected Individuals: Immunizations and Antimicrobial Prophylaxis to Prevent First Episodes of Opportunistic Disease in Adults |
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Hepatitis B vaccine should be given in hepatitis B surface antigen and antibody-negative patients who have
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continued risk factors for hepatitis B because of the increased risk for chronic hepatitis in HIV-infected patients. Although data on the efficacy of other killed or inactivated vaccines is not available, it is still recommended that routine vaccines such as tetanus be given to HIV-infected patients.
Live attenuated vaccines such as polio, typhoid, and yellow fever should not be given. Measles vaccine, however, has been shown to be safe in HIV-infected children and can be given according to the recommendations for HIV-negative people. For details regarding dosages and schedules of immunizations, see Chapter 18.
Antimicrobial Prophylaxis
Table 39.11 delineates recommendations for antimicrobial prophylaxis for infections caused by Pneumocystis jiroveci (previously known as P. carinii), Mycobacterium avium, and Toxoplasma gondii. These indications for prophylaxis are guided largely by CD4 counts and not symptomatic infection. Recommended prophylaxis regimens for other opportunistic infections, initiated after episodes of symptomatic infection, are found below (Symptomatic Human Immunodeficiency Virus-Infected Patient).
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TABLE 39.12 Risks and Benefits of Delayed or Early Initiation of Therapy in the Asymptomatic HIV-Infected Patient |
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The most common side effects with TMP-SMZ prophylaxis, in descending order of frequency, include rash, pruritus, nausea and vomiting, fever, anemia, neutropenia, and elevated liver enzymes. These side effects generally occur within the first month of starting therapy, but some, especially cutaneous reactions and fever, may occur later, even years after initiation of therapy. These side effects occasionally necessitate discontinuation of therapy. Often, however, TMP-SMZ can be reintroduced, especially when given in gradually increasing doses using the liquid formulation.
If life-threatening reactions occur, such as Stevens-Johnson syndrome, or if the patient is unwilling to restart TMP-SMZ because of prior side effects, dapsone, aerosolized pentamidine, or atovaquone can be substituted. The major toxicities of dapsone are rash and cytopenias; it is also associated with the uncommon, but serious, complications methemoglobinemia and hemolysis. The side effects of aerosolized pentamidine (300 mg every 4 weeks administered over 20 to 25 minutes with a jet nebulizer) include cough and bronchospasm, most often seen in smokers or in patients with pre-existing asthma. Pretreatment with a metered-dose bronchodilator often prevents this problem. Additionally, because of the risk of aerosolization of a mycobacterial infection not previously suspected, aerosolized pentamidine should be used only in specially designated areas and in patients proven not to have active TB. Atovaquone is another oral alternative to TMP-SMZ but is much more expensive than the other prophylactic agents (~$10,000 a year). Side effects of atovaquone include rash and diarrhea.
All HIV-infected patients with positive tuberculin tests (defined as 5 mm or more of induration), regardless of age, should be treated prophylactically with isoniazid 300 mg for at least 9 months or rifampin and pyrazinamide for 2 months (19). The rifampin and pyrazinamide combination has been associated with cases of severe hepatotoxicity and even death; generally it should be avoided, especially for patients receiving other hepatotoxic drugs and those with a history of alcoholism or chronic liver disease. If this combination is used, it is recommended that liver enzymes be checked at baseline and after 2, 4, and 6 weeks of treatment (19a). If the patient is known to have been exposed to a strain that is resistant to isoniazid but sensitive to rifampin, rifampin should be used as preventive therapy (see details inChapter 34).
Patients with antibodies to T. gondii and CD4 cell counts less than 100 cells per cubic millimeter should be given TMP-SMZ (one double-strength dose per day) for
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prophylaxis (19). Dapsone and pyrimethamine are acceptable alternatives if TMP-SMZ is not tolerated. Folinic acid is also given, with the regimen at 25 mg/week to prevent bone marrow toxicity associated with pyrimethamine.
Prophylaxis is recommended against M. avium complex (MAC) when CD4 cell counts are less than 50 cells per cubic millimeter, and has been shown to reduce the risk of disseminated infection and overall mortality (23). Effective regimens include azithromycin 1,200 mg once a week, clarithromycin 500 mg twice daily, or rifabutin 300 mg daily. Azithromycin and clarithromycin are more efficacious than rifabutin, and azithromycin has the added advantage of once-weekly dosing.
Oral ganciclovir has been shown to reduce the risk of CMV retinitis in patients with low CD4 cell counts (24), but because of toxicity and difficulty defining which patients are at risk, primary CMV prophylaxis is not routinely recommended (19). However, ophthalmologic screening every 6 months for CMV retinitis is recommended for patients with CD4 cell counts less than 75 cells per cubic millimeter.
Fluconazole has been shown to reduce the risk of invasive fungal infections (esophageal candidiasis and cryptococcosis) for patients with advanced AIDS (CD4 counts <50 per milliliter), but does not reduce overall mortality (25). For this reason, and because of concerns about the development of drug resistance, the routine use of fluconazole as prophylactic agent is not recommended (19).
Since the advent of new antiretroviral agents that can raise CD4 cell counts for prolonged periods (see Antiretroviral Treatment section), there has been increasing evidence that primary (and in some cases secondary) prophylaxis can be discontinued once the CD4 cell count rises above the value used as the threshold for initiation. Discontinuation of primary prophylaxis for P. jiroveci, T. gondii, and MAC has been shown to be safe when patients have a sustained increase in CD4 counts above the prophylaxis threshold.
Coexisting Medical Problems
HIV-positive patients are as likely as HIV-negative patients to have common acute or chronic diseases. The two groups should be approached in the same way in addressing these problems and in addressing indicated preventive care (see Chapter 14).
Many HIV-infected patients describe minor problems, such as fatigue, night sweats, mild chronic diarrhea, pruritus, and low-grade temperature elevation, for which specific infectious causes cannot be identified. Many of these problems may be manifestations of chronic HIV infection. In addition, for some patients, a focus on somatic concerns is the way in which they present their mental distress (seeChapter 21 for a detailed discussion of somatization). When an identifiable opportunistic infection has been excluded (see Symptomatic HIV-Infected Patients section) and there is no evidence of a conventional infection, simple palliative measures should be recommended. Patients should be encouraged to discuss their mental distress at the same time that they are queried and advised about physical symptoms.
Psychosocial and Ethical Aspects
Dealing with the psychosocial issues accompanying the diagnosis of asymptomatic HIV infection is often more difficult than the medical management. Patients who have learned they have a fatal disease that may have been acquired sexually and is stigmatizing for a variety of reasons usually feel extremely isolated and despondent. Because patients’ emotional responses may impair the ability to process information, it is important to check their comprehension of the facts, to be prepared to reiterate points covered in the posttest counseling session (Table 39.6), and to respond to the feelings and questions that these points will evoke. The patient must understand how the virus is and is not transmitted, the usual course of the disease, and available therapeutic interventions.
The HIV-infected patient has an intense need for hope and support. In addition to ensuring the patient of ongoing support and using counseling techniques that are helpful for a patient in crisis (see Chapter 20), it is appropriate to offer psychologic or psychiatric consultation after the diagnosis of HIV infection. Among the possible psychosocial consequences of this diagnosis are the uncovering of homosexuality in men whose gay orientation has been confidential; the threatened loss of family, social, and occupational relationships; an increase in the release of irresponsible promiscuity in antisocial people; and an increased risk of suicide. These problems particularly require expert counseling.
HIV-positive patients should be assured of confidentiality about their condition but at the same time should be instructed to inform others who may have been infected by them. Although asymptomatic HIV infection is not reportable in most jurisdictions, the patient's physician may have a responsibility to inform others who may be infected if the patient will not do so. This raises the difficult conflict between the patient's right to confidentiality and the rights of other people to protect their health. Laws governing physicians’ actions and obligations and ethical aspects of caring for an HIV-infected patient are discussed further in a later section (Public Health and Legal Responsibilities of the Physician).
Antiretroviral Treatment
Multiple clinical trials have shown that HAART dramatically increases CD4 counts, decreases viral load, delays clinical progression, and prolongs life. However, the duration of the efficacious effect and the optimal stage for
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initiation of therapy are unknown. Development of resistance and long-term side effects of antiretrovirals are concerns in patients on HAART. The long-term side effects include dyslipidemia (dysmorphic changes and hyperlipidemia), hyperglycemia, and peripheral neuropathy. Concerns about these toxicities and uncertainty about the benefits and risks of early versus delayed initiation of HAART (Table 39.12) resulted in extensive revision of consensus recommendations for antiretroviral treatment in 2001. Table 39.13 shows consensus guidelines for antiretroviral treatment that were updated in October of 2004. Most importantly, patients must be willing and able to comply with HAART with the recognition that a very high level of compliance with medication regimen is necessary to prevent viral resistance and treatment failure. Table 39.14 shows strategies for optimizing adherence. Treatment recommendations updated in October 2004 and summarized in Table 39.15 include treatment with at least three agents, usually two nucleoside reverse transcriptase inhibitors (NRTI) with a nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (26). These guidelines are frequently revised; updated recommendations are available from the U.S. government (website: http://www.AIDSinfo.nih.gov).
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TABLE 39.13 Indications for the Initiation of Antiretroviral Therapy in the Chronically HIV-Infected Patient |
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Baseline viral loads and CD4 counts give the most useful information about prognosis without treatment. The CD4 count has increasingly been viewed as the guide for deciding on when to initiate HAART. The viral load is the best guide for monitoring the effectiveness of therapy and deciding when to change antiretroviral therapy. Once HAART is initiated, achieving an undetectable viral load should be the goal. In clinical trials, this is achieved in more than 80% of patients after 1 year of therapy, whereas in most clinical settings it is achieved in only 40% to 60% of patients.
Antiretroviral Drugs
The development of agents that act at different loci in the viral replication cycle has led to the application of principles used with other infectious agents to prevent resistance and promote eradication, such as the principles applied in the treatment of TB. The hallmark of these principles is the use of several agents simultaneously.
There are currently three classes of antiretroviral drugs used for initial treatment: NRTIs; the NNRTIs, which have the same mechanism of action as the NRTIs but a different structure; and the protease inhibitors, which act at a different locus in the process of viral replication than NRTIs or NNRTIs. There is also a fourth class of medications, fusion inhibitors, of which only one drug, enfuvirtide (Fuzeon), is currently available. This agent must be given as a twice-daily subcutaneous injection and currently is only used as a salvage treatment in combination with other
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effective drugs. Table 39.16 summarizes practical information on the most commonly utilized antiretroviral drugs, those that are included in the 2005 guidelines for initial treatment.
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TABLE 39.14 Strategies to Improve Adherence |
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Because many agents are available, there are many ongoing trials to determine which particular combinations are most efficacious for lowering the viral load. With several agents being used simultaneously, there is a high likelihood of side effects and drug–drug interactions. Because of the rapid pace at which these new drugs and the related clinical trial data are released, primary care providers should consult sources of timely updates (see http://www.hopkinsbayview.org/PAMreferences) or consult an expert when making decisions regarding antiretroviral therapy.
Overall Strategies in Antiretroviral Treatment
The viral load and CD4 count are both used to monitor the patient's response to therapy; however, the viral load is the guide for deciding on changes in antiretroviral therapy. Changes in CD4 count lag behind changes in viral load. Because patient compliance in taking HAART is crucial to avoid resistance, both verbal and written patient instructions about dosages and intervals are essential.
When HAART is initiated or changed, the viral load should be monitored 2 to 4 weeks later and then at 3-month intervals to assess continued efficacy. A 1.0 log decrease in viral load (e.g., from the hundreds of thousands to tens of thousands) should be achieved after 2 to 4 weeks of therapy. Patient compliance should be reviewed whenever there is a failure in suppressing viral load to an undetectable level. A transient increase in viral load, which resolves after about 1 month, may follow vaccine administration or an intercurrent acute illness.
When the viral load fails to suppress or rebounds to a detectable level, resistance to one or more drugs is likely. Compliance should be reviewed with development of strategies to improve adherence. Resistance testing should be performed to assess which of the antiretrovirals has lost effectiveness because of viral mutations
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(27) (see Drug Resistance section).
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TABLE 39.15 Recommended Regimens for Initial Antiretroviral Treatment (Choose One from Each Column). |
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TABLE 39.16 Characteristics of Antiretroviral Medications Recommended for Initial Treatment of HIV-1 Infection |
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Drug Resistance
It is now understood that loss of the antiviral response to HAART (as indicated by increased viral load and decreased CD4 count) is usually caused by the virus’ ability to mutate. The best way to prevent development of resistance is to maximally suppress viral replication and to sustain this; the only other way is to not expose the patient to antiretroviral medications in the first place (particularly if the patient is not ready for the commitment that HAART requires). A mutation that confers resistance to a specific antiretroviral agent may also result in resistance to similar drugs that have never been used. Thus, knowledge of the cross-resistance patterns of various antiretroviral agents is important in changing therapy.
Resistance mutations are random events, and the chance that a particular mutation will appear rises with the level of viral replication. The development of resistance is directly related to a patient's compliance in taking the prescribed dosage at the appropriate time. Taking antiretrovirals at a reduced dosage results in drug levels at which selection for drug-resistant variants can occur. Likewise, taking only one or two antiretrovirals increases the chance that the virus may become resistant to one or both. Resistance testing is most useful in two situations: for patients with a persistently detectable viral load while on HAART to guide therapy changes, and for those who are recently infected to detect transmission of resistant virus (27). Some experts recommend resistance testing be done on all newly diagnosed HIV-infected patients. However, resistance testing only gives reliable information about drugs a patient is currently taking; a patient may have virus with resistance mutations to certain drugs (particularly if they have been exposed to them previously), which may not be detected in the absence of the selective pressure of taking that drug.
Genotypic resistance testing is now easily available through many major laboratories. The test is costly 300 to 500 dollars), but this expense is negligible when compared with the cost of continuing ineffective antiretroviral medications. The viral load usually has to be above 1,000 copies per milliliter for the test to be performed, and the results are generally reported as a series of mutations identified by a letter-number-letter sequence (e.g., M184V). The number is the codon where the mutation has been detected, the first letter is the wild-type amino acid at that codon, and the last letter is the amino acid that has been substituted for it (e.g., M184V is a replacement of methionine with valine at the 184 codon). Interpretation of genotypic resistance testing is complex because some isolated mutations confer high-level resistance to a medication, whereas in other cases multiple mutations or specific combinations of mutations are needed for resistance to develop. Updated databases of resistance mutations are available through a number of Internet sites, including the one maintained by the International AIDS Society-USA (http://www.iasusa.org). Results of resistance testing must be considered in conjunction with knowledge of what antiretrovirals the patient has taken in the past. If noncompliance is contributing to resistance, a new HAART regimen should not be prescribed until obstacles to compliance are addressed and resolved.
Symptomatic Human Immunodeficiency Virus-Infected Patients
General Principles
The most important aspect of the primary care of the symptomatic HIV-infected patient is building rapport and trust with the patient. Many newly diagnosed HIV-positive patients are young and have been previously healthy; symptoms and illness are often new to them. They may either overreact to each symptom or deny symptoms entirely. Good rapport with patients is thus essential for having them disclose information and for distinguishing the significance of new symptoms.
The CD4 lymphocyte count is the most useful marker for making treatment decisions in the care of HIV-infected patients. Importantly, it serves as a guide for generating a differential diagnosis for symptoms. When a patient's CD4 count is greater than 500 cells per cubic millimeter, new symptoms are most likely to be due to non–HIV-associated conditions. When a patient's CD4 count is between 200 and 500, new symptoms should lead to a careful search for a possible HIV-related illness. Finally, when a patient's CD4 count is less than 200, new symptoms are more likely to be because of an opportunistic infection.
Human Immunodeficiency Virus Complications
The four most common AIDS-indicator conditions are PCP, disseminated MAC, esophageal candidiasis, and the HIV wasting syndrome. With widespread use of prophylaxis, the first two conditions have become less common. Most complications of HIV can be diagnosed and treated in ambulatory settings with only severely ill patients requiring hospitalization. This section briefly addresses the approach to the most common HIV-related complications; more information is available in the resources listed at http://www.hopkinsbayview.org/PAMreferences.
Constitutional Manifestations and Lymphadenopathy
Fatigue is probably the most common symptom described by HIV-infected people. Causes of fatigue include high levels of HIV virus in the blood, anemia, testosterone
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deficiency, medication side effect, and depression. The first three causes may be diagnosed by blood test. In the case of high levels of virus in the blood, HAART may ameliorate symptoms of fatigue. Anemia may be treated with once-weekly injections of erythropoietin, and testosterone deficiency may be treated with testosterone replacement by patch or injection. Fatigue related to medications often improves after the first few weeks of therapy but may warrant a change in medication. Chapter 24 outlines treatment of depression.
Fevers, night sweats, or weight loss may be the presenting manifestations of an opportunistic infection or a malignancy or they may be because of HIV infection itself. When one or more of these symptoms are present, the patient should be carefully evaluated for a treatable problem. Some constitutional symptoms (e.g., fever or diarrhea lasting longer than 1 month) categorize the patient as having symptomatic HIV infection. The laboratory evaluation of fever, chills, or night sweats should include a complete blood count (CBC) with differential, liver tests, chest radiograph, urinalysis, serum cryptococcal antigen test if CD4 count is near or below 200, blood cultures, and sputum cultures if sputum is available. If the history, physical examination, and these screening laboratory data do not reveal an explanation for fever, a more extensive workup should be performed. Considerations should be given to obtaining blood cultures for MAC if the CD4 count is less than 100 and to looking for an occult infection using computed tomography (CT) of the chest and/or abdomen. Disseminated MAC infection typically causes weight loss and spiking fevers in the absence of other specific symptoms. A drug-related fever should also be considered, with sulfa drugs a common offender.
Lymphadenopathy may represent reaction to HIV, infection with another agent, or a malignancy. Generalized lymphadenopathy (defined as nodes 1 cm or greater in diameter in two or more noncontiguous extrainguinal sites) may persist during the first 6 months after diagnosis of HIV. Most often enlarged are anterior and posterior cervical, axillary, submental, and femoral nodes; preauricular and epitrochlear nodes are rarely enlarged. Patients with generalized lymphadenopathy often have one or more other abnormalities in the history, physical examination, or laboratory evaluation, but no single abnormality coexists predictably with adenopathy. Lymphadenopathy per se has not been found to be predictive of the patient's future course.
If a patient's lymphadenopathy is most pronounced in the inguinal region, with or without an active genital lesion or a history of a lesion, STDs such as chancroid or lymphogranuloma venereum should be considered. If lymphadenopathy is localized in one area, progressively enlarging, associated with constitutional symptoms, or of a different texture (very firm or irregular), biopsy should be considered to exclude malignancy, especially non-Hodgkin lymphoma.
Respiratory Tract Manifestations
HIV-infected patients with a high CD4 count, presenting with cough, most often have a simple bronchitis. If the chest radiograph of an HIV-infected patient shows a lobar infiltrate, sputum should be obtained and processed for a Gram stain and routine culture. Mycobacterial and fungal stains and culture should also be considered. With the widespread use of PCP prophylaxis and HAART, Streptococcus pneumoniae(pneumococcus) has become the most common cause of pneumonia in HIV-infected individuals. Treatment of lobar pneumonia should be based on guidelines for empiric treatment of pneumonia, described in Chapter 33, unless or until a specific pathogen is identified.
Pneumocystis jiroveci (carinii) Pneumonia
Before widespread use of Pneumocystis prophylaxis, many HIV-infected patients experienced at least one episode of PCP in the course of their disease. Compared with other pneumonias, the symptoms of PCP are usually less acute in onset and sputum is usually scant and thin. Common complaints include fever, night sweats, dyspnea, and nonproductive cough. Dyspnea is most often the predominant or sole symptom. The duration of respiratory symptoms is usually 1 to 3 weeks, although the systemic symptoms may have been present for several months. Because many of these patients have been previously healthy, their clinical presentation may be subtle. For example, it is common for a patient with PCP to have had no more than a mild dry cough and a modest decrease in exercise tolerance. Thrush may be present or may have occurred in the past as an indicator of immunosuppression. The physical examination is often nonspecific. Fever, tachycardia, and tachypnea may be present and, if so, indicate more severe disease. Auscultation of the chest is often unremarkable, and the chest radiograph may be normal in up to 15% of cases.
HIV-infected patients with only a history of respiratory symptoms should undergo a stepwise laboratory evaluation that is designed to diagnose or rule out PCP and other pulmonary infections. Ambulatory pulse oximetry performed in the office provides objective evidence for whether oxygen desaturation is responsible for symptoms of dyspnea. Chest radiograph should be performed if pneumonia is clinically suspected. In patients with abnormal chest radiographs, the pattern of infiltrates is helpful in determining the next step. A lobar infiltrate on radiograph and a history of acute onset of symptoms is most consistent with a community-acquired pneumonia, either typical (e.g., pneumococcal) or atypical (e.g., mycoplasmal). A
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lobar infiltrate in the presence of subacute or chronic sym-ptoms is more consistent with mycobacterial or fungal disease. A diffuse interstitial pattern is the most common presenting pattern on a chest radiograph in patients with PCP.
In the presence of pneumonia or hypoxia, an attempt should be made to make a specific diagnosis by inducing the production of sputum.Pneumocystis is diagnosed by microscopic examination of sputum, either by silver stain or direct fluorescent antibody. Examination of induced sputum for Pneumocystis has a sensitivity of approximately 80% in selected patients, although its negative predictive value is low. Therefore, if a specific diagnosis is not made on induced sputum, the patient should undergo fiberoptic bronchoscopy with bronchoalveolar lavage. Sputum can also be stained and cultured for mycobacteria, fungi, and viruses.
Patients who are not hypoxic can be safely treated in the ambulatory setting using oral medications. There are several options for ambulatory treatment: the first-line agent for the treatment of PCP is TMP-SMX (15 mg/kg/day of TMP + 75 mg/kg/day of SMX in three to four divided doses for 21 days). The typical adult dose is two double-strength tablets three times a day. If the patient is allergic to or unable to tolerate TMP-SMX, dapsone with TMP (15 mg/kg/day of TMP + 100 mg/day of dapsone for 21 days) or atovaquone (750-mg suspension orally twice a day with meals for 21 days) may be used. Symptomatic improvement usually occurs within 24 to 48 hours, but it may be slower in some patients. The chest radiograph may take several weeks to revert to normal. Patients should not be considered to have failed treatment until at least 5 to 7 days of therapy without improvement have elapsed. At this time, discontinuation of the initial therapy and substitution of an alternative drug is warranted. Of patients with first episodes of PCP, over 90% recover. Higher mortality rates are seen in patients who develop severe hypoxemia. Secondary prevention for Pneumocystis should be instituted after the acute episode.
Tuberculosis
Mycobacterial infections are well-recognized complications of immunosuppression. The incidence of M. tuberculosis, which is highly communicable, is increasing in patients with AIDS, and TB may be the presenting illness in some HIV-infected patients. To reflect this, the 1993 CDC case definition for AIDS added pulmonary TB as an AIDS-indicator condition (Table 39.8). Chapter 34 discusses the approach to prophylaxis and treatment of TB in HIV-infected patients, including patients infected with multidrug-resistant strains of M. tuberculosis.
Neurologic Manifestations
The nervous system is often involved in patients with HIV infection. More than 10% of patients with AIDS have an initial AIDS-indicator neurologic disease (Table 39.8). Neurologic manifestations can affect the peripheral or central nervous system (CNS) and may be categorized as disease secondary to HIV infection itself, disease secondary to opportunistic pathogens or neoplasms, or disease related to medication toxicity.
Peripheral Neuropathy
Peripheral neuropathies occur at all stages of HIV infection. When caused directly by HIV, symptoms usually present as a distal symmetric sensory neuropathy. Neuropathy also commonly occurs as a toxic side effect of several of the antiretroviral medications, most notably stavudine and didanosine—again, usually a distal sensory neuropathy. Neuropathy due to these medications may resolve with discontinuation of the medication but often persists even after discontinuation. Symptoms of peripheral neuropathy may be controlled with tricyclic antidepressants or some of the antiseizure medicines, including gabapentin and lamotrigine (see Chapter 92). When symptoms are related to medication toxicity, treatment often requires a change in HAART regimen. HIV-infected persons are also at increased risk for Bell palsy and varicella zoster, even at high CD4 counts.
Global Central Nervous System Disorders Caused by Human Immunodeficiency Virus
In later stages of HIV infection, many patients develop the AIDS dementia complex, a disorder characterized by cognitive, motor, and behavioral dysfunction. Dementia is the most common CNS complication of AIDS and is included in the CDC case definition of AIDS (Table 39.8). Diagnostic features include positive HIV serology, history of cognitive/ behavioral changes (especially impaired concentration and attention, apathy, and memory loss), and associated neurologic findings including hyperreflexia, hypertonia, signs of myelopathy (spastic paraparesis or ataxia), and frontal release signs (28). In early stages of HIV infection of the CNS, the mental status and neurologic examinations can be completely normal. Cerebrospinal fluid (CSF) findings are nonspecific: normal or slightly elevated protein concentration, normal glucose concentration, and a slight mononuclear pleocytosis. CT or magnetic resonance imaging of the brain may show cerebral atrophy with changes in white matter.
Before making a working diagnosis of AIDS dementia, it is important to exclude metabolic or toxic encephalopathies, opportunistic infections, neoplasms, and neurosyphilis. The Mini-Mental Status Examination is helpful for identifying cognitive abnormalities in a brief office interview (see Chapter 26, Table 26.1). In a patient whose Mini-Mental Examination is normal, neuropsychologic testing may be useful in assessing suspected early
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AIDS dementia and in following the course of the disease. This may be especially important in assessing patients whose work requires a high level of cognitive function. Characteristic abnormalities include difficulty with complex sequencing, impairment of fine and rapid motor movements, and slowed verbal fluency. In rare instances, brain biopsy may be indicated to exclude other metabolic, neoplastic, or infectious causes. In patients with high viral loads, cognitive function may improve after initiation of HAART.
Opportunistic Central Nervous System Infections
The clinical presentation of opportunistic CNS infections may be subtle. Headache and fever are the most common presenting symptoms of CNS infections, although fever may not be present. Focal neurologic findings and meningismus are found in fewer than half of patients with CNS infection. Therefore, a high index of suspicion must be maintained in any HIV-positive patient with a low CD4 count with new onset of severe headache, a change in a usual headache pattern, or persistent headache. Because sinusitis may present with fever and a headache and is common in HIV-infected patients, this diagnosis should be considered as well.
Opportunistic infections of the CNS generally occur in HIV-infected patients with CD4 counts below 200. Cryptococcus neoformans is the most common pathogen causing meningitis in AIDS patients; this meningitis usually presents as a nonfulminant process. Focal CNS disease is most often caused by T. gondii, although primary CNS lymphoma, tuberculoma, or cryptococcoma may present in the same way. Progressive multifocal leukoencephalopathy may also present as a focal CNS disease. This is a progressive demyelinating disorder caused by reactivation of a papovavirus in immunosuppressed patients, including those with AIDS. It presents as a subacute disease, progressing over several weeks, with focal neurologic deficits without alteration of consciousness until its terminal stages.
Because the physical examination usually is not diagnostic, a thorough laboratory evaluation is important in any patient with new neurologic symptoms. The evaluation should begin with magnetic resonance imaging or contrast-enhanced CT of the head to exclude mass lesions. The presence of a ring-enhancing lesion is characteristic for toxoplasmosis, although lymphoma and other causes cannot be excluded. Because toxoplasmosis is the most common cause of such a lesion and because definitive diagnosis requires a brain biopsy, it is reasonable to begin empirical treatment for toxoplasmosis (usually with oral pyrimethamine, folinic acid, and sulfadiazine) on the basis of the CT. If after 10 to 14 days of therapy the patient has not improved clinically or the CT shows no improvement, further diagnostic measures should be considered.
Unless the CT shows a mass lesion that might lead to herniation, lumbar puncture should also be performed in evaluating new CNS symptoms. CSF should be evaluated for opening pressure, cell count, protein and glucose concentrations (with a simultaneous serum glucose), Gram stain, India ink preparation, culture for bacteria, mycobacterial and fungal stains and cultures, cryptococcal antigen, and a serologic test for syphilis. Cryptococcal meningitis may be present even with few or no cells in the CSF; in most cases, cryptococcal antigen is present in both the CSF and the serum. A working diagnosis of neurosyphilis should be considered in the presence of a positive serum Venereal Disease Research Laboratory (VDRL), CSF pleocytosis, and negative cultures and stains for other organisms, even if the CSF VDRL is negative. Once opportunistic infections and neoplasms are excluded, especially in a patient in whom mental status changes are pronounced, the AIDS dementia complex should be the working diagnosis.
Psychiatric Manifestations
Psychiatric disorders may predate the acquisition of HIV infection in some patients, and treatment of patients with a pre-existing psychiatric illness and HIV infection may be extremely challenging. Virtually all HIV-infected patients go through a stressful experience upon learning that they are infected. In the months to years that follow diagnosis of HIV infection, patients may require supportive counseling and the assistance of professional social workers and social service agencies to deal with psychosocial problems. Over the course of their illness, many patients develop symptoms of depression. Apathy and mental slowing are often prominent in the presentation of major depression in HIV-infected patients, and paranoid thoughts or other symptoms of functional psychosis may accompany symptoms that suggest delirium or cognitive impairment.
For major depression, which is more common in HIV-infected persons than in the general population, antidepressant treatment is usually effective. The usual dosages of all antidepressants are appropriate for patients in the early stages of HIV infection. The dosages should be lower than the usual recommended dosages in patients who are in the late stages, and these patients seem to be more sensitive to all of the effects of antidepressants. (See Chapter 24 for practical information about antidepressants.) Psychostimulant drugs (e.g., methylphenidate) may be helpful in alleviating the apathy in depressed HIV-infected patients.
For patients who develop psychotic symptoms, the high-potency neuroleptic haloperidol is recommended because it has few anticholinergic side effects. Psychotic symptoms in HIV-infected patients respond to low dosages of haloperidol (e.g., 1 to 5 mg one to three times a day).Chapter 25 has details regarding the use of neuroleptic drugs.
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Oral Cavity and Gastrointestinal Manifestations
The oral and GI manifestations of HIV infection may be caused by opportunistic pathogens or, in the case of some patients with diarrhea, by nonopportunistic pathogens.
Oral Lesions
Oral lesions are common in HIV-positive patients and are often the first symptoms of immunodeficiency. The most common oral problem is thrush, or candidiasis, which occurs most typically as a whitish coating of the oral mucosa or tongue and affects half of patients at some point in their disease (see Chapter 112, Fig. 112.6). Other manifestations of oral Candida infection are angular cheilosis and erythema without coating. Mycostatin liquid (500,000 units swish and swallow five times a day) or clotrimazole troches (10 mg five times a day) usually control symptoms of thrush. Symptoms usually resolve within 10 to 14 days of treatment; if they fail, systemic therapy with fluconazole 100 mg daily for 10 to 14 days should be used.
Other oral manifestations of HIV infections include oral hairy leukoplakia, KS, mass lesions secondary to neoplasms and opportunistic infections, and aphthous ulcers. Oral hairy leukoplakia presents as symptomless, hypopigmented shaggy lesions on the lateral aspects of the tongue, which histologically show hyperparakeratosis of the mucosa. It may be confused with thrush, but unlike thrush, it cannot be wiped off the mucosa; scraping the lesion and examining the scrapings microscopically after application of potassium hydroxide may also be helpful (see technique, Chapter 117). The absence of typical fungal forms generally excludes thrush. Oral KS appears as bluish, black, flat lesions, usually on the hard palate.
Esophagitis
Esophagitis should be considered when the patient complains of odynophagia, dysphagia, or retrosternal chest pain. The most common cause of esophagitis in HIV-infected patients is Candida albicans; most patients have oral thrush concomitant with or preceding esophagitis. Candida infection distal to the oral cavity constitutes an AIDS-indicator condition. Esophagitis may also be caused by herpes simplex virus or CMV. Less commonly, aphthous ulcers, KS, primary lymphoma, and esophageal squamous cell carcinoma may be the cause of esophageal symptoms. In a patient with odynophagia, empiric treatment for candida esophagitis with oral fluconazole is indicated (200 mg orally the first day, followed by 100 milligrams per day). If symptoms do not improve within 7 to 10 days of treatment, the patient should be evaluated further with endoscopy.
Gastric and Hepatobiliary Diseases
The stomach is the most common GI location for visceral KS; lesions are commonly found by endoscopy. Most patients already have cutaneous KS. Gastric lymphomas may also be found. Acalculous cholecystitis occurs occasionally in HIV-infected patients. Sonography shows sludge in the gallbladder with edema of the gallbladder wall.
Parenchymal hepatic disease is common in HIV-infected patients, most often related to coinfection with hepatitis C. Commonly, elevated concentrations of serum alkaline phosphatase and serum aminotransferases are present. Hepatitis C often progresses more rapidly in the setting of coinfection with HIV (29). In patients with a good prognosis related to HIV, treatment with pegylated α-interferon and ribavirin for hepatitis C should be considered (see treatment of hepatitis C in Chapter 47). MAC is the most common opportunistic liver pathogen in patients with advanced HIV (CD4 <50). In MAC-related hepatitis, alkaline phosphatase levels are usually elevated out of proportion to other liver enzymes, and the diagnosis can be rapidly established by liver biopsy.
Diarrhea
Diarrhea occurs in many patients during the course of HIV infection (30). Additionally, many of the antiretroviral medications, especially the protease inhibitors, can cause symptomatic diarrhea. Large-volume diarrhea, often with associated crampy abdominal pain and weight loss, is commonly caused by both opportunistic and conventional enteric pathogens. G. lamblia, Salmonella, Shigella, and Campylobacter are possible causes of diarrhea in otherwise healthy patients with HIV. Pathogenic mostly in patients with low CD4 counts, I. belli, microsporidia, and cryptosporidium usually cause large-volume watery diarrhea in the absence of fever. CMV and MAC cause diarrhea in individuals with very low CD4 counts. Both are associated with fever, but patients with CMV colitis generally have more abdominal pain and bloody diarrhea compared with patients with MAC who usually have nonbloody diarrhea. Multiple stool specimens for culture and microscopic examination for ova/parasites and acid fast organisms (e.g., cryptosporidium) are necessary to diagnose these entities. Some entities, such as CMV and MAC, require more invasive procedures such as small- or large-bowel biopsy for diagnosis. When careful evaluation does not yield a cause (about one third of the time), diarrhea can be ascribed to HIV infection itself. Aggressive fluid resuscitation and the use of rice-based cereal are essential to prevent dehydration and wasting in patients, many of whom are already underweight. Chapter 35 contains details regarding the diagnosis and management of gastroenteritis caused by conventional pathogens.
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In patients who practice receptive anal intercourse, perianal herpetic ulcerations may account for proctalgia and tenesmus, as may a number of other sexually transmitted infections (e.g., syphilis, gonorrhea, and chlamydia). Chapter 98 provides a more detailed description of infectious lesions of the anus and rectum.
Human Immunodeficiency Virus Wasting Syndrome
The diagnosis of HIV wasting is made in patients with the combination of pronounced weight loss (10% or more from baseline) and either chronic diarrhea or chronic weakness and fever in the absence of other opportunistic infection or malignancy (31). Optimal use of antiretroviral drugs and therapy for lesions of the oral cavity and esophagus, in conjunction with good nutrition, is essential. Men should be evaluated for testosterone deficiency and treated with androgen replacement if abnormality is found (see Chapter 85). Underlying depression should also be considered.
Cutaneous Manifestations
Seborrheic dermatitis and psoriasis are the most commons cutaneous problems seen in HIV-infected patients. Chapter 116 describes diagnosis and management of these two conditions.
KS, which occurs mostly in homosexual men with HIV, is an AIDS-defining complication of HIV. KS presents as painless violaceous papules, usually 0.5 to 2 cm in diameter, often multiple, occurring most commonly on the face, on the extremities, and in the oral cavity. The lesions are bluish in light-skinned patients and may appear nearly black in dark-skinned patients. KS requires a biopsy for definitive diagnosis. KS may also involve the lungs, oral cavity, and the GI tract. The treatment of KS varies from the use of liquid nitrogen for skin lesions to the use of systemic chemotherapy for visceral involvement (32).
A number of the invasive opportunistic infections of HIV-infected patients, such as cryptococcosis, atypical mycobacterial infection, and histoplasmosis, may present with cutaneous lesions that are rather insignificant in appearance. In the presence of symptoms of systemic disease, one should be highly suspicious and consider biopsy of new skin lesions.
Mucocutaneous herpes simplex virus infection, described in Chapter 117, is another syndrome often seen in HIV-infected patients, and if persistent for more than a month is also an AIDS-indicator condition. Shingles, or reactivation of latent varicella-zoster infection, is also common in HIV-infected patients and may involve multiple dermatomes. Diagnosis is generally established by the typical appearance of grouped vesicles in a dermatomal distribution; cytologic examination of the vesicle fluid (the Tzanck smear), viral cultures, or polymerase chain reaction (PCR) may be helpful in some cases (see details in Chapter 117). The mucocutaneous erosions caused by these viruses also predispose the patient to local and disseminated bacterial superinfection. Chapter 117 summarizes diagnosis and treatment for herpes virus infections.
Other Organ Systems
Other organ systems are involved in HIV-infected patients, although not as often as those mentioned above.
Ophthalmologic
The predominant ophthalmologic disease is CMV retinitis, which may be completely asymptomatic but if left untreated progresses to blindness. The incidence of CMV retinitis has declined dramatically with the advent of HAART (33). Routine funduscopic examination is crucial, especially in patients with CMV disease in the past and those with CD4 counts below 100. Diagnosis is established by the typical appearance of the lesions, which are hemorrhagic and exudative.
Hematologic
Anemia occurs commonly in the late stages of HIV infection. It may be related to HIV infection itself or, less commonly, may be secondary to involvement of the bone marrow by one of the opportunistic infections, such as TB, MAC, or histoplasmosis. Anemia may also be secondary to medications, especially zidovudine and sulfa drugs. Anemia should be investigated as outlined in Chapter 55. Patients with advanced HIV and symptomatic anemia with low erythropoietin levels can be treated with erythropoietin injections. Thrombocytopenia may occur at any stage of HIV. It is usually immune-based, related to the HIV virus itself, and generally responds to treatment with antiretroviral therapy; in refractory cases, corticosteroids or splenectomy can be effective. Leukopenia occurs as a direct result of the HIV virus and can be exacerbated by medications. The most effective treatment of leukopenia is suppressing HIV replication with HAART. Granulocyte colony-stimulating factor (G-CSF) can be given if the absolute neutrophil count falls below 500 cells per cubic millimeter.
Renal
Both reversible and irreversible renal abnormalities are encountered in patients with HIV infection. Although some of these abnormalities may be caused by HIV infection,
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many result from identifiable causes, especially drug toxicity. HIV-related nephropathy reveals focal sclerosing glomerulonephritis on biopsy. Some patients respond to therapy with HAART; angiotensin-converting enzyme (ACE) inhibitors and corticosteroids may also be beneficial (34).
Cardiac
The diagnostic approach to cardiac disease in HIV-infected patients should also focus on identifiable causes other than HIV infection. A distinct HIV cardiomyopathy has been described. In such cases, HIV RNA has been isolated directly from myocytes. Coxsackie B virus, CMV, and toxoplasmosis are infectious causes of HIV-related cardiomyopathy (35). Additionally, HIV-infected patients on HAART appear to be at increased risk of atherosclerotic heart disease, likely due to the hyperlipidemia induced by many of these medications (particularly the protease inhibitors) (36); it is recommended that patients started on HAART have baseline and followup lipid panels checked. HIV-infected patients with hyperlipidemia are generally treated in the same way that uninfected patients are (see Chapter 82).
Gynecologic
With the increase in the numbers of HIV-infected women, involvement of the reproductive tract has been recognized. Women with HIV infection often have chronic vulvovaginal candidiasis or herpes, poorly responsive to therapy, as the first manifestation of underlying immunodeficiency. Immunosuppressed women may also be at more risk for the progression to malignancy of cervical papillomavirus infection. HIV-positive women should have an initial Pap smear, followed by a repeat in 6 months. If both are normal, followup Pap smears should be repeated every 12 months. All HIV-positive women with abnormal Pap smears should have colposcopy performed.
Problems Unique to Specific Patient Populations
Injection Drug Users
Injection drug users have difficult medical and social problems, even in the absence of HIV disease. Hospital admission for complications related to drug use, including endocarditis, thrombophlebitis, and cellulitis, is common. Thus, when an injection drug user is infected with HIV, the care becomes even more challenging.
Many individuals engaging in substance abuse can be compliant with complicated HAART regimens. Because the patient's best chance of durable success is with his initial HAART regimen, poor compliance can be disastrous in the long run. Compliance with office visits is a useful predictor for likely compliance with HAART. Therefore, it may be best to delay initiation of HAART in patients with substance abuse problems until individuals show up for at least two consecutive office visits (this may be a good strategy for all patients).
If a patient continues to use drugs and miss office visits, referral to a treatment program, including methadone maintenance, might be beneficial. It is important to note that drug interactions occur between methadone and several antiretrovirals, most notably the NNRTIs, that results in increased clearance of methadone. Patients on methadone and started on an NNRTI usually need their methadone dose raised. Additionally, one of the NNRTIs, efavirenz, may give a false positive result for marijuana on a urine drug screen. Chapter 29describes treatment of substance abuse.
Women
Most women infected with HIV in the United States are injection drug users or are sexual partners with men who have a history of injection drug use. Many women in the latter group may not know their partner has put them at risk and do not find out about their HIV diagnosis until they are pregnant or symptomatic. Barrier contraception (condom use by the partner) is of paramount importance to prevent not only pregnancy but also transmission of HIV (for details, see Sexual Transmission, above). Antiretroviral therapy during pregnancy reduces the risk of transmission of HIV to the fetus and thus should be prescribed to pregnant HIV-infected women (see Perinatal Transmission, above) (12). Efavirenz (teratogenic) and the combination of stavudine and didanosine (hepatotoxicity and lactic acidosis) should be avoided during pregnancy.
Special Considerations
Social and Economic Issues
Patients with AIDS are faced not only with coping with a fatal disease, which is sexually transmissible, but also with the social stigma attached to the disease. These patients must confront the need to inform their sexual partners (for the partners’ own protection), the risk of losing close friends, and isolation from their family. They must also face the risk of employment, housing, or insurance discrimination. Women must face the effect of this disease on their childbearing future, as well as the effect on children they are already rearing.
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HIV infection is also a financial burden for most patients. The cost of antiretroviral medications alone exceeds $10,000 annually and even those who have private health insurance may be saddled with high co-payments or may exhaust their pharmacy coverage. Patients who are disabled from the complications of this illness may qualify for Social Security disability. This means that the patient receives Social Security income immediately but must wait 24 months before receiving Medicare health insurance. A patient who meets the needs criteria for Supplemental Security Income can obtain health insurance through Medicaid immediately (see Chapter 9 for further information). In the United States, there are a number of other programs that help to provide medical care for HIV-infected patients. The Ryan White Comprehensive AIDS Relief Emergency (CARE) act was first enacted in 1990 and provides funding for HIV care through a number of mechanisms, including grants to states, cities, and health care providers. State-administered AIDS drug assistance programs (ADAPs) provide funding for medications for patients who do not have access through other programs; coverage and access to this program vary from state to state.
A newer and rather unusual problem that has arisen since the advent of HAART is patients having unexpected health restored after years of considering themselves to be terminally ill. This has raised many psychologic and practical issues, including making plans for a future never expected, returning to work after being on disability, and the guilt of surviving when so many did not earlier in the epidemic.
In addressing the social aspects of the patient's disease, the patient's right to privacy and confidentiality should be ensured at the outset, and patients should be asked to specify the people to whom they plan to disclose the nature of their illness. Many AIDS patients require counseling to cope with these decisions and the many changes in their lives caused by their disease. In addition to provider input, the supportive counseling of a social worker or nurse educator and help from community-based support groups should be enlisted.
Death and Dying
Because AIDS is still a fatal disease in many, dealing with the issues of death and dying is extremely important. It is probably not appropriate to begin such discussions when a patient first learns of the HIV diagnosis other than to answer questions about the prognosis frankly. It should be emphasized that HIV infection has a long latency period. Hope is extremely powerful in maintaining the patient's psychological and physical well-being.
The more appropriate time to explore the issues of death and dying is when the patient develops signs and symptoms related to progressive disease. Open discussions should be initiated about financial planning and about advance directives regarding resuscitation and other aspects of care when one may not be competent. These discussions should take place early in the course of AIDS while the patient is still fully competent. Chapter 13 discusses issues of death, dying, and bereavement, and Chapter 12 describes legal considerations in specifying and documenting advance directives.
Public Health and Legal Responsibilities of the Physician
No disease in recent times has emphasized to a greater extent the confrontation between the defense of individual privacy and the protection of public health. Clearly, this remains a major challenge to health care professionals dealing with HIV infection. The physician's primary responsibility is to the patient. The unique trust inherent in the physician–patient relationship allows the physician to guide the patient to protect those who may be at risk because of sexual contact. The physician has the responsibility of emphasizing to the patient, on multiple occasions if necessary, the importance of informing sexual or needle-sharing partners. Guidelines governing the physician's responsibility when the patient refuses to inform others are included in many state laws, and advice regarding these guidelines should be sought from state public health authorities. Many states now have confidential programs for sexual partner notification.
Physicians are required by law to report all newly diagnosed cases of AIDS, using confidential morbidity report forms. In addition, some states now require reporting of most symptomatic HIV-associated diseases.
Information and Support for Household Members
People who live with or care for HIV-infected patients at home have special needs. Most importantly, they need clear information about the transmission of HIV infection, about both the safety of nonintimate contact with the patient and the risks and precautions related to intimate contact. Household caretakers should be advised to follow the universal precautions recommended to health care workers for the care of all patients (Table 39.3).
People close to patients with HIV infection and AIDS invariably have a variety of intense emotional reactions and must also confront distressing social implications of the patient's illness. Thus, taking the time to share information and respond to questions from patients’ caretakers is a critical part of caring for patients with HIV and AIDS.
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Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
19a. Centers for Disease Control and Prevention. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection—United States, 2003. MMWR 2003;52:735.