The HIV-Positive Patient: the Initial Treatment

Florida Heart CPR* The HIV-Positive Patient: The Initial Treatment 3 hours

Objectives Upon completion of this course participants will be able to: 1. Discuss the role of resistance testing in newly diagnosed HIV- seropositive patients. 2. Recount the pros and cons of initiating antiretroviral therapy during primary HIV infection. 3. List the diagnostic tests and immunizations that should be considered for newly presenting HIV-positive patients. 4. Describe important considerations when deciding whether to initiate antiretroviral therapy in chronically infected patients. Introduction Since the HIV serologic test became available in 1984, allowing for early diagnosis of the disease before the onset of symptoms, HIV infection has been best managed as a chronic disease. This is even more true today, as highly active antiretroviral therapy (HAART) and opportunistic infection (OI) prophylaxis prolong survival and decrease HIV-related morbidity. The initial encounter between the HIV-infected patient and his or her healthcare provider is more than an opportunity for clinical data collection; it sets the stage for a partnership that may last for many years. The natural history of HIV infection encompasses a wide spectrum of disease, and at the initial visit the status of the patient's health may range from asymptomatic to advanced immunodeficiency. The outpatient evaluation should include a comprehensive intake history, physical exam, and laboratory tests that serve not only to stage the disease, but help the clinician to:  plan follow-up care and immunizations;  evaluate indications for OI prophylaxis;  determine the need for antiretroviral therapy; and,  review the patient's need for counseling, educational, and psychosocial support.

Case History The patient is a 28-year-old black woman who was found to be HIV infected during a recent hospitalization for community-acquired pneumonia. In consideration of this diagnosis and a history of unprotected heterosexual intercourse, she agreed to HIV antibody testing while in the hospital. HIV serology was reactive by both enzyme-linked immunosorbent assay (ELISA or EIA) and Western blot. The patient was informed of the diagnosis and was referred for outpatient evaluation and care.

Florida Heart CPR* HIV Initial Treatment 2

In the history obtained at the outpatient clinic, the patient stated that before the diagnosis of pneumonia she had been feeling generally well but had experienced more frequent episodes of vaginal yeast infections and some fatigue. Her normal weight was 140 lb, but she had recently lost approximately 10 lb. The patient attributed to her weight loss to pneumonia. She also reported fever, night sweats, chest pain, and cough in the days before her hospitalization. The patient denied diarrhea, new skin lesions, difficulty swallowing, visual changes, or headache. In the weeks since discharge from the hospital, she noted increasing fatigue, poor appetite, and insomnia. On further questioning, she admitted to frequent crying and a loss of interest in her work. Her medical history is significant for recurrent genital herpes. She had the "usual" childhood diseases, but does not know whether she had chicken pox. Her only surgery was an appendectomy at age 12. She has been pregnant twice and has 2 children, aged 6 and 8 years. Both children were delivered by uncomplicated spontaneous vaginal delivery. The patient states the children are healthy. Her only current medication is ibuprofen as needed. She has completed a course of levofloxacin for treatment of the pneumonia without recurrence of her symptoms. The patient is a clerical worker employed full time. She is a native of Baltimore, and her only travel has been in the Mid-Atlantic area and New York. She is unmarried and lives with her two children and her mother. She denies exposure to tuberculosis and reports that her last purified protein derivative (PPD) skin test was in grade school and was negative. She smokes cigarettes but does not drink alcohol and has never used drugs. Her only sexual partner in the past 10 years is the father of her children, with whom she has been estranged for approximately 1 year. To her knowledge, he is not HIV-infected or at risk for HIV infection. When they were together, they did not use condoms. She has made plans to inform him of her diagnosis. The patient has informed her mother of her health status but not her children.

Diagnosing HIV Infection Identifying Patients at Risk Because a large number of HIV-infected individuals are unaware of their infection, it is critical that all clinicians assess risk for HIV and offer testing when appropriate. In the early years of the AIDS epidemic surveillance focused on members of high-risk groups (gay and bisexual men, injection-drug users, and hemophiliacs), but that approach has become much less useful as the epidemic has expanded. It is now more helpful to think in terms of "risk behaviors" rather than "risk groups." The taking of a thorough history, including nonjudgmental but specific questioning about sexual activity and drug use, has become even more important in identifying patients at risk for HIV infection. HIV testing should be performed for any patient who requests it. Other indications for voluntary testing include sexually transmitted diseases, pregnancy, and active tuberculosis. Testing should be considered in young adults with shingles or women with refractory or recurrent vaginal candidiasis. Voluntary testing is also recommended for adults hospitalized in facilities where the seroprevalence exceeds 1% or where the AIDS case rate exceeds 1 per 1000 discharges. Finally, HIV testing should be considered in patients with generalized lymphadenopathy; unexplained dementia,

Florida Heart CPR* HIV Initial Treatment 3 aseptic meningitis, or peripheral neuropathy; chronic, unexplained fever, diarrhea, or weight loss; generalized herpes simplex or multidermatomal herpes zoster infection; unexplained cytopenias; B-cell lymphoma; or other opportunistic conditions suggestive of defective cell-mediated immunodeficiency. Diagnosis Unfortunately, the diagnosis of HIV disease may still lead to social stigmatization, loss of health insurance, and discrimination in employment and housing. Because of the potential consequences to the patient, informed consent is recommended before HIV testing and is required in most states. In addition, HIV testing should be accompanied by pre- and posttest counseling, which should include discussion of the purpose of the test, prognosis and natural history of HIV infection, transmission of HIV and risk reduction, partner notification, and other medical and social issues related to the diagnosis. The criteria for a positive HIV test are a repeatedly positive EIA followed by a positive Western blot, usually requiring the presence of gp120/160 plus gp41 or p24.[1,2] The accuracy of the HIV serology is extremely high. The initial screening test for HIV infection is an EIA, which is highly sensitive. A negative EIA does not require confirmation with Western blot. False-negative results are uncommon and usually occur during the window period between infection and seroconversion. The average time from infection to a positive EIA is 10-14 days. Most individuals will have seroconverted within 3-4 weeks, and the window period rarely exceeds 6 months. False-positive results (ie, with both EIA and Western blot) are extremely rare and most often are due to clerical errors. Patients with a positive ELISA and a single band on Western blot are reported as indeterminate. Indeterminate tests may occur in seroconverting patients, patients with advanced HIV disease, patients with HIV-2 infection, and patients with alloantibodies (pregnancy, transfusions, or organ transplantation) or autoantibodies (collagen-vascular diseases, autoimmune diseases, malignancy). Although patients in low-risk categories with indeterminate tests are unlikely to be infected, a repeat test at 3-6 months is usually performed for confirmation. If the indeterminate test is due to seroconversion, it will usually become positive within 1 month. Other methods to detect HIV infection include polymerase chain reaction (PCR) tests, p24 antigen assays, and viral isolation.[1] However, because of the accuracy of standard HIV antibody testing, these techniques are rarely necessary, except when primary infection is suspected. A rapid test for HIV antibodies (Single Use Diagnostic System [SUDS]; Abbott/Murex) has been approved but is not currently commercially available. It is comparable in accuracy to the EIA. It is highly sensitive, so a negative result is definitive and can be reported within several minutes. Specificity is lower, however, and all positive results must be confirmed with standard tests. Primary HIV Infection Primary HIV infection, or the acute retroviral syndrome, refers to the symptom complex that occurs in 80% to 90% of infected patients following infection with HIV. The typical time from exposure to onset of symptoms is 2 to 4 weeks, but rare cases have been reported in which symptoms are delayed by several months. While most symptomatic patients seek medical consultation, the diagnosis is often missed because the

Florida Heart CPR* HIV Initial Treatment 4 symptoms are nonspecific. Typical symptoms include fever, lymphadenopathy, pharyngitis, erythematous maculopapular rash, and myalgias or arthralgias. Some patients may report headache or gastrointestinal symptoms. Hepatosplenomegaly or thrush may be noted in some cases. Some patients present with neurologic findings, such as aseptic meningitis, meningoencephalitis, peripheral neuropathy, facial palsy, or Guillain-Barré syndrome.[3] Laboratory findings include lymphopenia followed by lymphocytosis, and atypical lymphocytes may sometimes be seen. There is usually a transient decrease in CD4+ cell count, although the patient's baseline count is not usually known in such cases.[4] In some cases, CD4+ cell depletion may be more severe. Such patients are at risk for opportunistic infections, such as Pneumocystis carinii pneumonia (PCP). The HIV serology is usually negative or indeterminate in patients with primary infection. The diagnosis is best established with the quantitative plasma HIV RNA assay (the standard viral load test)[5] or the qualitative HIV DNA assay. Patients experiencing the acute retroviral syndrome generally have marked viremia; the viral load usually exceeds 100,000 copies/mL and often exceeds 1 million copies/mL. Low viral loads should not be considered diagnostic of HIV infection, since false positives can occur at low levels. Detection of HIV RNA or DNA in plasma is more sensitive than the p24 antigen for the diagnosis of primary infection, though the p24 antigen is less expensive. A new strategy for diagnosing recent HIV infection involves the use of both a sensitive and less sensitive, or "detuned," assay. Because HIV antibody levels increase during the first few months after seroconversion, recent seroconverters will test positive on a standard sensitive ELISA assay but will test negative on a less sensitive assay. This test is not yet commercially available, but is being used in clinical studies to distinguish between recent seroconverters and those with long-standing HIV infection. It is critical that the primary care or emergency physician considers the diagnosis of primary infection when appropriate and performs the necessary tests to make the diagnosis. Primary HIV infection should always be considered in patients presenting with febrile illnesses resembling mononucleosis or other nonspecific viral syndromes. There is evidence that early intervention with antiretroviral therapy may prevent the loss of specific anti-HIV cellular immunity (see below).[6] Moreover, patients experiencing primary infection are highly infectious because of high-level viremia. It is important that they be diagnosed during this stage so that they can be counseled about risk reduction. Finally, patients who are diagnosed during the acute retroviral syndrome can be tested for acquired drug resistance using genotype or phenotype assays. The transmission of resistant virus, including virus with resistance to multiple drugs and drug classes, has now been well described throughout the industrialized world. It has also been shown that transmitted resistance affects response to subsequent antiretroviral therapy.[7] A resistance test performed at this stage is likely to detect the resistance pattern of the infecting viral strain. With time, resistant virus will be overgrown by wild-type virus, and resistance tests will be less sensitive at detecting acquired resistance. The results of early resistance assays may be useful in guiding therapy, even if treatment is deferred for many years. The question of whether to treat patients who present during or shortly after primary infection remains controversial. Current US Department of Health and Human Services

(DHHS) guidelines[8] recommend antiretroviral therapy for patients with acute infection or within 6 months of seroconversion. This recommendation is based on evidence that early treatment may prevent the loss of HIV-specific cellular immunity that occurs in most chronically infected patients.[6] There are also data supporting the benefit of "structured treatment interruptions" (STIs) in patients treated during or shortly after acute infection.[9] However, the duration and number of courses of therapy required to achieve this result are unclear. If lifelong antiretroviral therapy were required, there would be no clear clinical benefit associated with the preservation of the immune response. Because of the potential for drug toxicity, decreased quality of life, and premature drug resistance, patients diagnosed and treated early would be at a potential disadvantage compared with those who were diagnosed during chronic infection and chose to defer treatment. To answer these questions, it is critical that patients be diagnosed during primary infection and referred to appropriate clinical trials. Because the benefits are hypothetical, early therapy should be avoided in patients who are ambivalent about treatment or their ability to adhere to antiretroviral therapy. The Initial History and Physical Exam Patient's Health History Clinicians evaluating HIV-infected patients for the first time should take a careful history, focusing specifically on common HIV-related symptoms, including fevers, night sweats, weight loss, diarrhea, skin rashes or lesions, oral thrush or ulceration, and changes in neurologic function or mental status (Table 1). Patients should be questioned about their medical history, with special attention to sexually transmitted diseases, chicken pox or shingles, viral hepatitis, bacterial infections, gynecologic problems, and exposure to tuberculosis. It is important that the history also include questions about where the patient has lived and traveled. For example, patients reporting travel in endemic areas for histoplasmosis (Ohio and Mississippi River valleys) and coccidioidomycosis (Southwestern deserts) may be at risk for reactivation disease, even after moving to nonendemic areas. Patients should also be questioned about behaviors that might lead to further transmission of HIV. Specifically, a sexual history should be taken to assess the patient's current sexual practices and to determine whether sexual partners are aware of the patient's HIV status and have been tested for HIV. Patients should be encouraged to inform their partners of their HIV status. The healthcare professional can offer to help with this difficult but necessary task. Release of this information could compromise the patient's physical safety and may detrimentally effect supportive family relationships. Laws vary from state to state regarding the obligation of healthcare providers to notify sexual partners, and clinicians should be aware of such laws in their own jurisdiction. Active injection-drug users should be asked about their drug-using practices, their source of needles, whether they share needles, and if so, with whom. Depression is common in HIV-infected patients, and clinicians should be alert to the possibility of this treatable condition. Since newly diagnosed patients may assume that depression is an inevitable consequence of learning their HIV status, they may not volunteer their symptoms. The history should include questions focusing on changes in mood, libido, sleeping patterns, appetite, concentration, and memory. Patients should also be specifically asked about whom they have informed of their HIV status, how they

Florida Heart CPR* HIV Initial Treatment 6 have been coping with the diagnosis of HIV infection, and what kinds of support they have been receiving. It is important to know about their family, living situation, and work environment, and how they have been affected by the diagnosis of HIV infection. Many patients at this stage may benefit from counseling or participation in support groups. In the course of taking a complete history, the clinician can begin to assess the patient's level of awareness about HIV infection and treatment, evaluating the patient's educational needs, and determining the form that such support might take. A variety of topic-focused educational materials geared to varying educational levels are an invaluable resource, since much of the verbal education that frequently takes place during initial visits may be lost as a result of the informational and emotional overload that often accompany such encounters.

Case History (continued) On physical examination, the patient is a somewhat anxious but healthy-appearing woman in no distress. She is afebrile, with normal vital signs. She weighs 132 lb. Her fundi are normal, and she has no thrush or oral hairy leukoplakia. She has bilateral anterior cervical and axillary lymphadenopathy. Her chest is clear. There are no murmurs, rubs, or gallops. Abdominal exam is unremarkable, with no hepatosplenomegaly. Pelvic exam revealed moderate Candida vaginitis but was otherwise unremarkable. Neurologic exam was nonfocal. She has mild facial seborrheic dermatitis, but no other skin rashes or lesions. The Physical Exam A complete physical examination should be performed on all patients at the time of the initial encounter (Table 2). Patients should be questioned about how their current weight compares with what they consider their normal or baseline weight. Special attention should be paid to the examination of the skin, looking for evidence of seborrheic dermatitis, Kaposi's sarcoma, folliculitis, fungal infections, psoriasis, and prurigo nodularis. Fundoscopic examination should be performed, and in patients with advanced HIV disease (CD4+ cell count < 100 cells/mm3), it may be appropriate to refer the patient to an ophthalmologist for a dilated slit-lamp examination to screen for cytomegalovirus (CMV) retinitis. The oropharynx should be carefully examined, noting evidence of candidiasis, oral hairy leukoplakia, mucosal Kaposi's sarcoma, aphthous ulceration, and periodontal disease. Although persistent generalized lymphadenopathy (PGL) is common among HIV-infected patients, it does not correlate with prognosis or disease progression. Localized lymphadenopathy or splenomegaly, however, may be a sign of infection or malignancy, and should be evaluated further. It is important to perform a careful anogenital examination for evidence of sexually transmitted diseases, including condylomata and herpes simplex lesions. HIV-infected women demonstrate high rates of vaginal candidiasis, cervical dysplasia, and pelvic inflammatory disease, and a screening pelvic examination with Pap smear is mandatory. Women with abnormal Pap smears or a history of infection with human papillomavirus (HPV) should be referred for colposcopy.

The neurologic examination should include a general assessment of cognitive function. Patients in whom dementia is suspected may benefit from more sensitive neuropsychologic testing. Laboratory Studies A number of initial laboratory studies should be performed in patients presenting with HIV infection (Table 3). Patients who have no documentation of their HIV serology results or who were tested anonymously should have a repeat HIV test. It is sometimes appropriate to repeat the HIV serology even for patients with documentation of a positive serology, especially for individuals who are asymptomatic and demonstrate normal CD4+ cell counts and undetectable viral loads. While the HIV serology (EIA with confirmatory Western blot) is extremely accurate and specific, false-positive test reports have occurred. These reports are virtually always the result of clerical error rather than a problem with the test itself. Viral Load Assays Quantitative virology, or "viral load" testing, is an essential and standard part of the evaluation of an HIV-infected individual. Viral load testing is used to assess prognosis, determine the need for antiretroviral therapy and the type of antiretroviral therapy required, and to define a baseline laboratory value so that the response to therapy can be measured.[8] Viral load assays include the HIV RNA PCR (Amplicor HIV-1 Monitor, Roche Laboratories), the branched chain DNA or bDNA (Quantiplex HIV RNA assay, Chiron), and the nucleic acid sequence-based amplification or NASBA (Advanced BioScience Laboratories/Organon Teknika). Thresholds for detection range from 200- 400 copies/mL for the standard assay to 20-40 copies/mL for the ultrasensitive assays. The standard assay should be ordered in the initial evaluation of the untreated patient. The ultrasensitive assay should be reserved for patients whose viral loads are expected to be low. Viral loads tend to be highest (105-107 copies/mL) during the acute retroviral syndrome and advanced disease. Asymptomatic patients commonly demonstrate lower viral loads (102-105 copies/mL). Viral loads may be increased by intercurrent illness or recent vaccination, and measurement should probably be deferred in such cases. CD4+ Cell Counts The CD4+ cell count is essential in the management of HIV-infected individuals. The CD4+ cell count is used to stage HIV disease, to help establish the risk of specific HIV- associated complications, to determine the need for opportunistic infection prophylaxis, to assess response to antiretroviral therapy, and -- increasingly -- to determine the need for therapy. It is important that the clinician and patient be aware of the substantial variation in the results of CD4+ cell counts. Factors affecting the CD4+ cell count include:  seasonal and diurnal variation;  the use of corticosteroids;  intercurrent illness;  coinfection with HTLV-I;

 inter- and intralaboratory variation; and,  variation in the components of the white blood cell count. Since in most laboratories the absolute CD4+ cell count is determined by multiplying the white blood cell count, the percentage of lymphocytes, and the percentage of CD4+ lymphocytes, variation in any one of these components can affect the total CD4+ cell count. Although the CD4+ percentage is not subject to variation based on the complete blood count (CBC) and differential, the clinical trials that are used to guide HIV therapy have consistently used the absolute CD4+ cell count, and therefore the CD4+ percentage is less frequently used clinically. In some cases, however, such as when the white blood cell count or lymphocyte count is unusually high, the CD4+ percentage may provide a more accurate reflection of the patient's immunologic status. Total CD4+ cell counts of 200 and 500 cells/mm3 generally correspond to CD4+ percentages of 14% and 29%, respectively. The use of the CD4+/CD8+ ratio is no longer advocated. New technologies are available that allow more direct determination of the absolute CD4+ cell count, eliminating the variability due to the other components of the CBC. The CD4+ cell count is used to determine the risk of specific HIV-related complications (Table 4). Patients with counts in the normal range (> 500 cells/mm3) are usually asymptomatic, although women may have more recurrent or severe Candida vaginitis, and PGL can occur at any stage of HIV infection. Pulmonary tuberculosis, bacterial pneumonia, Kaposi's sarcoma, and systemic non-Hodgkin's lymphoma also occur at all stages, although they become more frequent at lower CD4+ cell counts. Patients with CD4+ cell counts between 200 and 500 cells/mm3 are also at risk for herpes zoster, oral thrush, cervical intraepithelial neoplasia, idiopathic thrombocytopenic purpura (ITP), and anemia. AIDS-indicator conditions are unlikely at this stage, with the exceptions of Kaposi's sarcoma, non-Hodgkin's lymphoma, and the 3 indicator conditions added by the 1993 Centers for Disease Control and Prevention (CDC) case definition: recurrent pneumonia, tuberculosis, and invasive cervical carcinoma. Most opportunistic conditions occur when the CD4+ cell count falls < 200 cells/mm3. These include PCP, disseminated herpes simplex virus infection, disseminated histoplasmosis and coccidioidomycosis, miliary or extrapulmonary tuberculosis, and cryptosporidiosis. Toxoplasmosis and cryptococcosis require even greater immunosuppression, typically occurring at CD4+ cell counts < 100 cells/mm3, and disseminated M avium complex (MAC), and CMV end-organ disease are usually restricted to patients with CD4+ cell counts < 50 cells/mm3. In addition to the CD4+ cell count, other surrogate markers have been used in the evaluation of HIV infection. These include the p24 antigen and acid-dissociated p24 antigen, neopterin, and beta-2 microglobulin. Although all correlate with disease progression or activity in large cohort studies or clinical trials, they are less useful in the clinical management of individual patients. The ability to measure quantitative HIV RNA through quantitative virology has further decreased the utility of these tests in the management of HIV-infected individuals. Complete Blood Count and Chemistry Panel Anemia, leukopenia, and thrombocytopenia are common in HIV-infected individuals, and are readily detected with a complete blood count (CBC). As discussed earlier, the

CBC is also used to calculate the total CD4+ lymphocyte count. A chemistry panel is an important tool in the evaluation of the patient's nutritional status, to rule out HIV- or drug- related renal insufficiency and to diagnose liver damage due to alcohol or viral hepatitis. The CBC and the chemistry panel also provide baseline information that is necessary before the initiation of therapeutic agents that may have myelosuppressive or hepatotoxic effects. Syphilis Serology A nontreponemal test for syphilis, such as a VDRL or RPR, should be performed at baseline and repeated yearly due to the high rates of coinfection with HIV and Treponema pallidum. Biologically false-positive tests are not uncommon and can be excluded with a confirmatory fluorescent treponemal antibody test.[10] A lumbar puncture should always be performed if neurologic signs or symptoms are present at the time of clinical evaluation for a reactive lab result or if there is serologic evidence of treatment failure after therapy. Other indications are supported by more limited data, but most authorities recommend that a lumbar puncture be performed in all HIV-infected patients with late latent syphilis (> 1 year duration) or latent syphilis of unknown duration. Unfortunately, the interpretation of cerebrospinal fluid (CSF) findings can be difficult, since a nonreactive CSF VDRL does not rule out neurosyphilis, and the mononuclear pleocytosis and elevated CSF protein characteristic of neurosyphilis are also common manifestations of HIV infection. Tuberculosis Testing The CDC recommends routine testing with the PPD skin test (Mantoux, 5 TU units) for all HIV-infected individuals.[11] Annual testing should be considered for those at high risk for tuberculosis (TB). However, routine anergy testing is no longer recommended because of its variability, poor predictive value, and because prophylaxis in anergic individuals has been shown to prevent few cases of tuberculosis. Treatment of latent TB infection is recommended for all HIV-infected patients with: 1. a positive PPD (>/= 5 mm of induration); 2. a history of a documented positive PPD and no prior treatment of latent infection; or 3. close contact with a patient with active tuberculosis regardless of the skin test result. A chest radiograph should be obtained in any patient with a positive PPD. If the patient is symptomatic or has an abnormal chest radiograph, 3 sputum samples should be obtained for AFB culture to rule out active TB before initiating treatment of latent infection. It takes up to 2 months for M tuberculosis to grow in culture. Therefore, when suspicion for active TB is high, it is best to start 4-drug treatment for possible active disease while waiting for culture results. It should be noted that 5% to 10% of HIV- infected patients with pulmonary TB can have normal findings on chest radiograph. It is not necessary to obtain a chest radiograph in asymptomatic patients with negative PPDs for the purpose of ruling out TB. However, there may be other indications for a routine baseline chest radiograph in selected patients. For example, injection-drug users sometimes have radiographic abnormalities that may be mistaken for infiltrates. A

Florida Heart CPR* HIV Initial Treatment 10 radiograph obtained when the patient is asymptomatic may be useful for comparison during the evaluation of future respiratory complaints. Toxoplasma gondii Serology Serologic testing of patients for prior exposure to Toxoplasma gondii using the anti- Toxoplasma IgG is useful for evaluation of the need for specific prophylaxis against toxoplasmic encephalitis. This prophylaxis is now considered to be the standard of care according to the guidelines on preventing opportunistic infection released by the US Public Health Service and the Infectious Disease Society of America (USPHS/IDSA).[12] It is estimated that 20% to 50% of HIV-infected Toxoplasma-seropositive patients will develop toxoplasmic encephalitis; therefore, seropositive patients should receive prophylaxis against toxoplasmosis after their CD4+ cell count falls < 100 cells/mm3. Toxoplasma -seronegative adults, representing 70% to 90% of the US population, should be counseled on how to avoid new infection, primarily through the proper preparation of meat and the appropriate handling of cat litter. The serology should be repeated in previously Toxoplasma-seronegative individuals when their CD4+ cell count reaches 100 cells/mm3 if they are unable to take trimethoprim-sulfamethoxazole (TMP- SMX) for PCP prophylaxis. Although the Toxoplasma serology can never be used to diagnose or exclude toxoplasmosis, a seronegative patient with a space occupying lesion of the central nervous system is less likely to have toxoplasmosis than a seropositive patient. Viral Hepatitis Screening Vaccination against hepatitis B is appropriate for those patients without evidence of prior infection (negative anti-HBc or HbsAb), as chronic hepatitis is more common in HIV-infected individuals and patients may continue to engage in high-risk activities. Screening for chronic infection (HBsAg) is also reasonable.[12] It is also recommended that all HIV-infected individuals be screened for hepatitis C virus infection with an anti-HCV antibody.[12] Positive tests should be confirmed with an HCV RNA PCR or RIBA assay. Hepatitis A vaccine is safe for use in HIV-infected patients and should be considered in patients without prior exposure (negative total HAV antibody). Prevaccination screening is cost-effective when there is an HAV seroprevalence of over 30% in the population being screened. Current DHHS/IDSA guidelines recommend hepatitis A vaccination in all patients who are infected with hepatitis C because of the increased risk of fulminant hepatitis A in HCV-positive individuals.[12] Cytomegalovirus and Other Herpesviruses Serologic testing for CMV with the anti-CMV IgG serology is now recommended by the USPHS/IDSA guidelines, especially in those patients at lower risk of CMV infection (populations other than gay men or injection-drug users).[12] While seroprevalence rates among HIV-infected individuals are very high, the identification of seronegative patients allows for the use of CMV-negative or leukocyte-reduced blood products when transfusions are needed, thus reducing the risk of iatrogenic CMV infection. Although routine CMV prophylaxis is not currently recommended, CMV serology results may one day be helpful in determining appropriate prophylaxis.

It may also be valuable to obtain an anti-varicella IgG serology in patients who are unable to give a history of chicken pox or shingles. This baseline test will help to evaluate the need for postexposure prophylaxis with varicella zoster immune globulin in patients who are exposed to individuals with an acute varicella infection. Serologic testing for other herpesvirus infections is not recommended, as it has no diagnostic or therapeutic applications. Glucose-6-phosphate Dehydrogenase Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is a genetic condition that predisposes individuals to hemolysis following exposure to oxidant drugs. The drugs most commonly used in HIV-infected patients that can lead to hemolysis in G-6-PD- deficient patients are dapsone, primaquine, and sulfonamides. While there are many variants of G-6-PD deficiency, the most common are:  GdA-, which is found in 10% of black men and 1% to 2% of black women;  Gdmed, which is found predominantly in men from the Mediterranean, India, and Southeast Asia. The hemolysis associated with Gdmed can be life threatening, while those patients with the GdA- variant have milder, more self-limited hemolysis that may not preclude the use of the oxidant drugs. Routine screening for G-6-PD deficiency is sometimes recommended in patients with the appropriate genetic background. Individuals at risk should be screened either at baseline or before initiating therapy with an oxidant drug because G-6-PD levels may be falsely normal during episodes of acute hemolysis. HIV Resistance Testing Assays that measure genotypic or phenotypic resistance to antiretroviral agents are now commercially available. Because drug-resistant virus can be transmitted from one individual to another, it is now recommended that baseline resistance testing be considered in patients presenting during or shortly after the acute retroviral syndrome. [8,13] A resistance test performed at this stage is likely to detect the resistance pattern of the infecting viral strain. With time, resistant virus will be overgrown by wild-type virus, and resistance tests will be less sensitive at detecting acquired resistance. The results of early resistance assays may be useful in guiding therapy, even if treatment is deferred for many years. A baseline resistance test performed in a patient with chronic infection is only helpful if it is positive: An absence of mutations does not mean that the patient was not infected with resistant virus. As a result, the routine use of resistance tests in treatment-naive, chronically infected individuals is somewhat controversial. Gynecologic Tests HIV-infected women are at increased risk for a number of gynecologic problems, including pelvic inflammatory disease and tubo-ovarian abscesses, Candida vaginitis, and cervical dysplasia. The latter, a complication of infection with HPV, may be more aggressive and progress more rapidly as immunodeficiency progresses, and if untreated can lead to invasive cervical carcinoma, an AIDS-indicator condition. All HIV- infected women should have a baseline pelvic examination with Pap smear.[12] The use of routine colposcopy is controversial, but the test is clearly indicated in women with

Florida Heart CPR* HIV Initial Treatment 12 abnormal Pap smears or a history of genital condylomata. Pap smears should be repeated at least annually in asymptomatic women; more frequent evaluations are recommended in women with abnormalities on Pap smear or after treatment for cervical dysplasia, since recurrence is more common in HIV-infected women. Other Tests Because many antiretroviral agents cause increases in cholesterol and triglycerides, fasting lipid profiles should be drawn on all HIV-infected patients before starting therapy. It may be appropriate to check lipid profiles at baseline, regardless of the need for immediate therapy, as part of routine healthcare maintenance. HIV-infected patients are also at risk for hypogonadism, especially with more advanced disease. Whether antiretroviral therapy ameliorates or contributes to this condition is unclear. Clinicians should consider drawing a morning serum testosterone level to establish a baseline. A total testosterone level that is low or in the low end of the normal range establishes the diagnosis; however, if the results are normal, a free testosterone level is required to rule in or rule out hypogonadism. Other lab tests that may be indicated, depending on the age and sex of the patient, include a urinalysis, chest x-ray, electrocardiogram, thyroid-stimulating hormone, prostate specific antigen, or mammogram.

Case History (continued) Blood samples were sent for confirmatory EIA and Western blot, CBC, chemistry panel, CD4+ cell count, quantitative HIV RNA, VDRL, anti-Toxoplasma IgG, anti-CMV IgG, anti- HBc and HBsAg, G-6-PD level. A PPD skin test was placed, and a chest radiograph was ordered. The patient did not know whether she had ever had chicken pox, and an anti- varicella IgG serology was ordered.

Staging One of the goals of the initial evaluation of the HIV-infected individual is to determine the stage of disease. The most widely used staging system is the 1993 revision of the CDC's AIDS Surveillance Case Definition for Adolescents and Adults.[14] According to this system, individuals are assigned a stage according to a 3 x 3 matrix consisting of 3 CD4+ cell count categories and 3 clinical categories (Table 5). CD4+ cell count categories are as follows: Category 1: CD4+ cell count of at least 500 cells/mm3 or 29% Category 2: CD4+ cell count of 200-499 cells/mm3 or 14% to 28% Category 3: CD4+ cell count < 200 cells/mm3 or < 14% Clinical categories are as follows: Category A: documented HIV infection, asymptomatic, including PGL; or acute HIV infection Category B: symptomatic disease, conditions not listed in clinical category C, including conditions that are:

(a) attributed to HIV infection or indicative of a defect in cell-mediated immunity; or, (b) considered to have a clinical course or management that is complicated by HIV infection. Conditions such as bacillary angiomatosis; persistent or recurrent thrush; poorly responsive vulvovaginal candidiasis; moderate to severe cervical dysplasia; constitutional symptoms such as fever (38.5°C) or diarrhea more than 1-month duration; oral hairy leukoplakia; herpes zoster (> 1 episode or > 1 dermatome); ITP; listeriosis; PID; and peripheral neuropathy. Category C: AIDS indicator condition (Table 6). Once a Category C condition has occurred, the individual remains in Category C. According to the 1993 case definition for AIDS, individuals with stage A3, B3, C1, C2, or C3 infection, shown in bold in Table 5, have CDC-defined AIDS. Specifically, any individual with either an AIDS indicator condition or a CD4+ cell count < 200 cells/mm3 has AIDS. Once a diagnosis of AIDS has been made, for surveillance purposes it is not negated by subsequent developments (eg, individuals who are diagnosed with AIDS on the basis of a CD4+ cell count < 200 cells/mm3 are still considered to have AIDS if their CD4+ cell count subsequently returns > 200 cells/mm3, perhaps in response to antiretroviral therapy), even though the relevance of the diagnosis may then be more historical than clinical. While reporting requirements vary from state to state, all cases of AIDS must be reported to the local health department. Accurate and complete reporting is important to ensure that adequate resources are available as the amount of federal AIDS funding received by a city or community is frequently based on the number of reported cases from that region. Table 6. AIDS Indicator Conditions in the 1993 CDC Case Definition for AIDS (Adults)

 Candidiasis, of esophagus, trachea, bronchi or lungs  Cervical cancer, invasive*  Coccidioidomycosis, extrapulmonary*  Cryptococcosis, extrapulmonary  Cryptosporidiosis with diarrhea greater than 1 month  Cytomegalovirus of any organ other than liver, spleen, or lymph nodes  Herpes simplex with mucocutaneous ulcer greater than 1 month or bronchitis, pneumonitis, esophagitis  Histoplasmosis, extrapulmonary*  HIV-associated dementia: disabling cognitive and/or motor dysfunction interfering with activities of daily living*  HIV-associated wasting: involuntary weight loss > 10% of baseline plus chronic diarrhea (2 loose stools/day for 30 days) or chronic weakness and documented

enigmatic fever for 30 days*  Isosporiasis with diarrhea greater than 1 month*  Kaposi's sarcoma in patient younger than 60 years (or older than 60 years*)  Lymphoma of brain in patient younger than 60 years (or older than 60 years*)  Lymphoma, non-Hodgkin's of B-cell or unknown immunologic phenotype and histology showing small, noncleaved lymphoma or immunoblastic sarcoma  Mycobacterium avium complex or M kansasii, disseminated  Tuberculosis*  Nocardiosis*  Pneumocystis carinii pneumonia  Pneumonia, recurrent-bacterial (>/= 2 episodes in 12 months)*  Progressive multifocal leukoencephalopathy  Salmonella septicemia (nontyphoid), recurrent*  Strongyloidiasis, extraintestinal  Toxoplasmosis of internal organ

*Requires positive HIV serology

Antiretroviral Therapy As of April 2002, there are 16 Food and Drug Administration (FDA)-approved antiretroviral agents (Table 7), and others are sometimes available through expanded access programs. This allows for an enormous number of potential drug combinations. As the number of treatment options available to HIV-infected patients continues to grow, issues of drug-drug interactions and cross-resistance have made the management of HIV infection exceedingly complex. It is now recommended that HIV-infected individuals be managed by clinicians with HIV expertise. Expert care has been shown to prolong survival and to be more cost-effective than care by generalists.[15] Guidelines for antiretroviral therapy have been developed by the DHHS and the Henry J. Kaiser Family Foundation.[8] These guidelines are updated frequently and reflect the consensus of a panel of experts based on available data from clinical trials. However, these guidelines should not be viewed as a substitute for expert care. According to these guidelines, chronically infected patients for whom antiretroviral therapy is clearly indicated are those with symptomatic disease, and asymptomatic patients with CD4+ cell counts < 200 cells/mm3. Therapy is generally recommended in asymptomatic patients with CD4+ cell counts between 200 and 350 cells/mm3, though some controversy exists for this group because of the lack of clinical data demonstrating a survival benefit associated with initiation of therapy above a CD4+ cell count of 200 cells/mm3. Initiating therapy based solely on viral load measurements is even more controversial. The DHHS guidelines state that "some experts would recommend

Florida Heart CPR* HIV Initial Treatment 15 initiating therapy" in patients with CD4+ cell counts > 350 cells/mm3 who have HIV RNA values > 55,000 copies/mL. Others would defer therapy but monitor the CD4+ cell count more frequently. Based on concerns about resistance, quality of life, lack of evidence of benefit, and short- and long-term toxicity, there is little enthusiasm for treatment of patients with CD4+ cell counts > 350 cells/mm3 and HIV RNA levels < 55,000 copies/mL. Guidelines from the International AIDS Society-USA (IAS-USA) recommend treatment of patients with viral loads > 30,000 copies/mL regardless of CD4+ cell count, patients with viral loads between 5000 and 30,000 copies/mL who have CD4+ cell counts < 500 cells/mm3, and patients with CD4+ cell counts < 350 cells/mm3 regardless of viral load (Table 8).[16] Table 8. IAS-USA Recommendations on Criteria for Initiation of Antiretroviral Therapy CD4+ Cell Count Plasma HIV RNA Level (Copies/mL) 3 (cells/mm ) < 5000 5000-30,000 > 30,000 < 350 Recommend Recommend Recommend therapy therapy therapy 350-500 Consider therapy Recommend Recommend therapy therapy > 500 Defer therapy Consider therapy Recommend therapy The move in favor of deferred therapy has arisen for a number of reasons: (1) Eradication, the basis for the earlier "hit early, hit hard" approach, is no longer felt to be achievable with the currently available antiretroviral agents; (2) we are now more aware of a number of important long-term toxicities associated with antiretroviral therapy, and are concerned that patients will not be able to remain on these regimens indefinitely; (3) drug resistance and cross-resistance within the 3 available drug classes limits the treatment options of a large proportion of patients, especially those with less than perfect adherence; (4) clinical trials demonstrate that patients who start therapy with lower CD4+ cell counts (but > 200 cells/mm3) have a good clinical, immunologic, and virologic response to therapy and are unlikely to develop HIV-related complications while they wait to initiate treatment. Guidelines should never be viewed as treatment algorithms. Rigid adherence to guidelines has resulted in the premature treatment of patients who were not ready to start therapy. The rate of progression is a function of the CD4+ cell count and the viral load, which predicts the slope of the decline in CD4+ cell count. Patients with very low CD4+ cell counts cannot afford to defer therapy, but delaying therapy may be reasonable for those with a low risk of progression. The decision to start treatment must be made by the clinician and patient together, based on a careful weighing of the advantages and disadvantages. Antiretroviral therapy prevents the loss of immune function and allows for more effective immune reconstitution. Patients with baseline viral loads < 100,000 copies/mL respond better to

Florida Heart CPR* HIV Initial Treatment 16 most HAART regimens than those with higher viral loads, and therapy is also better tolerated by healthy patients. On the other hand, asymptomatic patients may become symptomatic as a result of side effects of therapy. Treatment serves as a daily reminder of infection at a time when some degree of denial might be psychologically beneficial. Should resistance develop, therapeutic options may be depleted prematurely. Those who start early cannot predict how they would have fared if left untreated. Finally, patients who start therapy cease to be treatment-naive, a condition associated with the best outcome in clinical trials. They commit themselves to the optimal strategy of the day, one that may seem flawed 6 months later. Too many patients have begun therapy without a complete understanding of the importance of adherence and the implications of resistance. As a result, many have exhausted their treatment options before they ever developed unequivocal indications for therapy. Antiretroviral therapy is rarely an emergency. Because extremely high levels of adherence are required to prevent drug resistance and treatment failure, it is critical that patients start therapy only after they have been counseled in detail about side effects, dosing instructions, and the importance of strict adherence.

Prophylaxis of Opportunistic Infections Patients present at all stages of HIV infection, and OI prophylaxis may be indicated based on initial laboratory testing. As mentioned earlier, the USPHS/IDSA have developed guidelines for prophylaxis of opportunistic infections.[12] Prophylaxis that is given the highest priority, and defined as the standard-of-care, includes prophylaxis against PCP, toxoplasmosis, and tuberculosis. Pneumocystis carinii Pneumonia Pneumocystis carinii pneumonia prophylaxis is indicated in individuals with CD4+ cell counts < 200 cells/mm3 (or < 14%), a history of PCP, oral thrush, or opportunistic or constitutional symptoms suggestive of advanced immunodeficiency. The drug of choice is TMP-SMX. Dapsone and aerosolized pentamidine are recommended as alternative agents. Atovaquone has been shown to be as effective as dapsone in the prevention of PCP. Toxoplasmosis Toxoplasmosis prophylaxis is indicated in individuals with CD4+ cell counts < 100 cells/mm3 who are seropositive for T gondii. TMP-SMX is adequate prophylaxis against toxoplasmosis; there is some evidence that full dose TMP-SMX (1 double-strength tablet daily) may be more effective than the lower doses commonly used to prevent PCP. Patients receiving dapsone for PCP prophylaxis should be given weekly pyrimethamine and leucovorin to improve activity against toxoplasmosis. Atovaquone, with or without pyrimethamine and leucovorin, may also be effective for prophylaxis of both toxoplasmosis and PCP. Aerosolized pentamidine provides no protection against toxoplasmosis and would not be a recommended agent for PCP prophylaxis in a Toxoplasma seropositive patient. Although both clarithromycin and azithromycin have in vitro activity against T gondii, data on their efficacy in preventing toxoplasmosis are insufficient.

Tuberculosis Treatment of latent infection (TLI) is indicated for individuals with a positive PPD skin test (at least 5 mm of induration) or for those with a history of a positive skin test who have not received TLI, regardless of age or stage of HIV infection. In addition, TLI is indicated, regardless of PPD status, for close contacts of active tuberculosis cases. The use of control skin tests ("anergy panels") and prophylaxis of anergic individual are no longer recommended. TLI should consist of 9 months of isoniazid with pyridoxine. Other options include 4 months of therapy with either rifampin or rifabutin, which has never been studied in HIV-infected individuals, or 2 months of therapy with daily pyrazinamide plus either rifampin or rifabutin. The daily 2-month rifampin/pyrazinamide regimen was well-tolerated by HIV-infected patients in the only study of this regimen, but it has been associated with severe hepatotoxicity and death in HIV-negative individuals; therefore, non-pyrazinamide-containing regimens may be preferred when adherence and completion of treatment can be assured. Mycobacterium avium Complex Mycobacterium avium complex prophylaxis is the standard of care according to USPHS/IDSA guidelines, based on studies demonstrating prolonged survival in patients who receive prophylaxis. MAC prophylaxis is indicated in individuals with CD4+ cell counts < 50 cells/mm3. The USPHS/IDSA guidelines recommend clarithromycin (500 mg twice daily) and azithromycin (1200 mg weekly) as first-line agents. Rifabutin (300 mg daily) is the alternative regimen. Cytomegalovirus Cytomegalovirus prophylaxis is not routinely recommended by the USPHS/IDSA guidelines, despite the FDA approval of oral ganciclovir for this indication. While oral ganciclovir appears to be effective in preventing CMV disease, it is vastly more expensive than other prophylactic therapies and has a more complex dosage schedule. In addition, the bone marrow toxicity of this agent often necessitates the use of growth factors. The FDA-approved indications for prophylaxis (CD4+ cell count < 50 cells/mm3 with positive anti-CMV IgG) may be excessively broad and would result in large numbers of patients being treated to prevent a relatively small number of cases. Studies are under way, however, to evaluate the use of laboratory tests, such as viral cultures, viral antigens, and quantitative CMV DNA PCR, that would indicate a high risk for the development of CMV end-organ disease. It is possible that such tests will allow clinicians to use oral ganciclovir or valganciclovir as preemptive therapy, resulting in more cost-effective prophylaxis. Fungal Infections Although fluconazole has been shown to decrease the risk of serious fungal infections (primarily cryptococcal meningitis and Candida esophagitis), fungal prophylaxis is not routinely recommended by the USPHS/IDSA guidelines. Cryptococcal meningitis is relatively uncommon compared with other preventable infections and is rarely a cause of death. Candida esophagitis responds rapidly to treatment (oral fluconazole), and therefore primary prophylaxis is not a high priority. In addition to drug interactions and cost, one of the primary drawbacks to routine antifungal prophylaxis is the potential for the development of azole resistance. While it is clear that resistance is associated with

Florida Heart CPR* HIV Initial Treatment 18 prior azole use, it has not been determined what aspects of therapy predispose to resistance. It is possible, for example, that the continuous utilization of fluconazole at low CD4+ cell counts will be found to be safe, provided that earlier use is minimized. Until these questions are answered, however, the most appropriate use of fluconazole appears to be for maintenance therapy or secondary prophylaxis of cryptococcal meningitis and recurrent Candida esophagitis. Immunizations Both cellular and humoral immunity wane with the progression of HIV infection, and the ability to form specific antibodies after infection or immunization becomes progressively impaired. It is therefore important that vaccinations be given as early as possible in the course of HIV infection. Alternatively, for patients presenting with moderate-to-advanced immunosuppression it may be preferable to defer vaccination until after antiretroviral therapy has been initiated in order to maximize the immunogenicity of the vaccine. In general, live-virus or live-bacteria vaccines should not be given to HIV-infected individuals. Specific contraindicated live vaccines include BCG, MMR, oral polio vaccine, oral typhoid vaccine (Ty21a), and yellow fever vaccine. Varicella zoster vaccine is a live virus vaccine, but it can be administered to asymptomatic or mildly symptomatic children, according to current USPHS guidelines.[12] If polio vaccination is indicated for HIV-infected individuals or their household contacts, the enhanced potency inactivated polio vaccine (eIPV) should be used. Measles vaccine is considered safe for nonimmune individuals, except for those who are severely immunosuppressed. Pneumococcal Vaccine The pneumococcal polysaccharide vaccine is recommended by the USPHS/IDSA Working Group,[12] because of the high incidence of pneumococcal pneumonia and bacteremia associated with HIV disease. The vaccine is given as a single dose (0.5 cc intramuscularly [IM]), and revaccination should be considered after 5 years or in a patient who was originally vaccinated with a CD4+ cell count < 200 cells/mm3 who subsequently had a rise in CD4+ cell count to > 200 cells/mm3 as a result of antiretroviral therapy. Influenza Vaccine The influenza vaccine is recommended by the Advisory Committee on Immunization Practices[17] and is recommended for consideration by the USPHS/IDSA Working Group. [12] It is given as a single dose of 0.5 cc IM annually, usually in October or November. This vaccine is administered to prevent influenza and its potential complications (primarily bacterial pneumonia) and to prevent clinical syndromes that may mimic more serious opportunistic infections. Although the data are conflicting, there is some evidence that influenza vaccination leads to a transient rise in viral load. Thus, the potential risk of increasing viral replication may outweigh the benefit of the vaccine, especially in patients with advanced HIV disease for whom vaccine efficacy is low. In contrast, patients with higher CD4+ cell counts receiving effective antiretroviral therapy may benefit from vaccination without significant risk of accelerating disease progression. These same considerations also may apply to other vaccines; however, the effect of influenza vaccine on viral load has been the most extensively studied. Hepatitis Vaccines

HIV-infected patients who are infected with hepatitis B virus are more likely to develop chronic infection. Therefore, patients without prior exposure may benefit from the hepatitis B vaccine if they remain at continued risk of infection. The ACIP recommends that the hepatitis B vaccine be offered to HIV-infected injection-drug users; sexually active gay men; prostitutes; sexually active heterosexual men and women with sexually transmitted diseases or more than 1 partner in the past 6 months; and household or sexual contacts of HBsAg carriers.[17] Recipients should first be screened for past infection using the HBsAb or anti-HBc serology. The USPHS/IDSA Working Group recommendations are similar.[12] The vaccine is given in a series of 3 IM injections at 0, 1, and 6 months using 20 mcg per dose of Energix B or 10 mcg per dose of Recombivax or combined with hepatitis A vaccine as Twinrix (see below). Hepatitis A vaccine can be given safely to HIV-infected patients at risk. It is recommended for HCV-infected individuals because of their greater risk of developing fulminant hepatitis A.[12] It should be considered in all nonimmune individuals, especially those who are traveling to an endemic area, sexually active gay men, injection drug users, or those exposed to a community outbreak. Prevaccination screening with total HAV antibody is recommended when the seroprevalence of HAV is greater than 30%. Hepatitis A vaccine can be given in the form of Havrix (1 cc IM at 1 and 6 months), Vaquta (1 cc IM at 1 and 6 months), or combined with hepatitis B vaccine as Twinrix (see below). A combined HAV/HBV vaccine (Twinrix) is now available. It is given using the same dosing schedule as the hepatitis B vaccine (1 mL at 0, 1, and 6 months). Haemophilus influenzae Type-B Vaccine Although there is an increased frequency of Haemophilus influenzae infections in adults with HIV disease, most are caused by non-type B infections, which are not covered by the H influenzae type-B vaccine. The protein-conjugated vaccine has been shown to produce the best immune response in early stage disease, while patients with late-stage disease respond better to the unconjugated vaccine. The efficacy of the vaccine has been more clearly established in children and is not given as a standard vaccine to HIV- infected adults. Tetanus-Diphtheria Vaccination Recommendations for the tetanus-diphtheria (dT) vaccine do not differ from those for immunocompetent adults. A single booster (0.5 cc IM) is given every 10 years for adults who completed the primary series. Vaccination for International Travel For international travelers, the inactivated (parenteral) typhoid vaccine or the typhoid Vi polysaccharide vaccine can be used in place of the live oral vaccine (typhoid Ty21a). Hepatitis A vaccine, Japanese B encephalitis vaccine, enhanced potency inactivated polio vaccine (eIPV), and hepatitis B vaccine can all be given safely when indicated. Cholera vaccine is safe for HIV-infected patients, but the vaccine has poor efficacy and is no longer recommended for travel to any country. The safety and efficacy of yellow fever vaccine in HIV-infected patients is unknown.[12] Follow-up Evaluation

The frequency of evaluation depends in part on the stage of HIV disease. Asymptomatic patients with normal CD4+ cell counts and low viral loads can be monitored infrequently, repeating CD4+ cell counts and viral load measurements every 3 to 6 months. Although HIV-related complications are unlikely at this stage, these visits are useful for addressing healthcare maintenance issues as an opportunity to provide education about the disease and the prevention of transmission, to prepare the patient for antiretroviral therapy, and to build the therapeutic relationship that will become increasingly important should the patient progress to more advanced disease. Once therapy has been initiated, it is appropriate to monitor the response to therapy every 4 to 6 weeks with a repeat CD4+ cell count and viral load measurement until the viral load has become undetectable. Laboratory tests can then be obtained at 3-month intervals to monitor for drug toxicity and treatment failure. CD4+ cell counts should be followed both for assessment of antiretroviral efficacy and to determine the need for opportunistic infection prophylaxis. However, in patients whose CD4+ cell counts are consistently < 50 cells/mm3, there is little utility in repeated testing except to monitor the response to a new antiretroviral regimen. It is important to educate patients about the meaning of the CD4+ cell count and viral load measurement in the context of the natural history of HIV disease. All too often, HIV-infected individuals place excessive emphasis on minor fluctuations in laboratory markers, becoming inappropriately despondent or elated over small changes that are well within the range of normal laboratory variation. This fixation may reflect the attitudes of clinicians and researchers, who may be more comfortable focusing on objective laboratory test results than with the other less quantifiable components that define the patient's health. The CD4+ cell count and viral load are markers that provide clinicians with an important but incomplete measure of the state of a patient's HIV disease and immunosuppression. Both patients and clinicians must maintain a holistic approach to HIV disease, which incorporates laboratory markers as only 1 component of the total picture. Still, it has become clear from numerous clinical trials that the goal of therapy in patients taking their first antiretroviral regimen should be maintenance of an undetectable plasma HIV RNA using an ultrasensitive assay (< 20-50 copies/mL).[8] This should be an achievable goal in an adherent patient without pre-existing drug resistance, and failure to achieve this goal is associated with the accumulation of drug resistance mutations and eventual treatment failure. Laboratory tests that should be repeated yearly include the VDRL, Pap smear, and in some cases the PPD. The influenza vaccine is also given yearly if indicated (Table 9).

Case History (continued) On the first visit, before the laboratory results were available, the possibility of depression was discussed. The patient admitted being anxious and preoccupied with thoughts of her eventual illness and death, and talked of her fears concerning the health and the future of her children. She expressed great concern that she might have "full- blown AIDS," and wondered how long she would be able to work. Arrangements were made for the testing of her children, although she was told that the fact that they were healthy at the ages of 6 and 8 meant that they were unlikely to be infected. The course of HIV disease and the potential benefit of antiretroviral therapy and opportunistic infection

Florida Heart CPR* HIV Initial Treatment 21 prophylaxis were discussed, and she was given topic-specific reading material to take home. The patient was given a topical antifungal preparation for her vaginal candidiasis and steroid and antifungal creams for her seborrheic dermatitis. After explaining the importance of advanced directives for everyone, regardless of HIV status or stage of illness, she was given forms and informational material on the Living Will and the Durable Power of Attorney for Health Care. She was referred to a case manager, who collected information on her financial and insurance status, personal resources, and living situation. The case manager provided the patient with information concerning support groups for HIV-infected women and referred her for short-term counseling for depression and stress. Special Issues in the Management of HIV-Infected Patients Although HIV infection shares many features of other chronic diseases, caring for HIV- infected patients also entails unique responsibilities. Frequent discussion of the avoidance of transmission is important. Primary caregivers often play a role in encouraging or assisting with the disclosure of the patient's HIV status. In many communities, practitioners will provide care for patients for whom substance abuse, mental illness, homelessness, child care, lack of medical insurance, and poverty are of more immediate concern than their HIV infection. Clinicians must be familiar with resources in the community that can assist their patients with these obstacles so that their medical problems can be addressed. In many cases, a key part of the initial visit will be a referral to a social worker or case manager who can help the patient access those resources. The initial encounter provides an appropriate opportunity for introducing the concept of advance directives, such as the living will and the durable power of attorney for healthcare. Discussing this issue in a routine fashion and explaining that it is an important consideration for everyone, regardless of HIV status, may result in considerably less anxiety than bringing it up later in the course of the disease, when the patient may assume that it is now being addressed because of a change in prognosis. During the initial encounter, the clinician can begin to educate the new patient about how to be a patient, including:  accessing emergency services;  obtaining laboratory results;  whom to speak with to schedule appointments; and,  what to do about insurance issues. The patient may already have case management services, but if not, a referral to case management should be offered. Caring for a drug-using HIV patient poses special challenges. Resources for drug treatment are limited in many communities, even for individuals actively seeking help with their addiction. Case managers can help such patients obtain drug treatment and can provide information on groups such as Narcotics Anonymous and counseling services. However, many substance abusers may seek care for their HIV infection but may not be interested in drug treatment. Such patients are more likely to be adherent

Florida Heart CPR* HIV Initial Treatment 22 with their medical care if they are treated in a nonjudgmental fashion. When substance abuse is addressed, it should be treated as a medical issue, not a moral one. Furthermore, it should not be assumed that active substance abusers are incapable of complying with medical therapy. While active substance abuse, including alcohol abuse, has been associated with nonadherence in many studies, some substance abusers are able to comply with therapy. Progress in the understanding and management of HIV disease takes place extremely rapidly, and patients expect their caregivers to maintain an up-to-date knowledge base of the latest advances in therapy. Patients may also ask for unapproved or experimental treatment or may take alternative therapies concurrently with or in place of standard drugs. Practitioners must be familiar with the potential risks and benefits of the alternative therapies that are in vogue in their community so that they can counsel their patients about the use of these therapies and monitor them appropriately should the patient choose to take them. A number of popular herbal supplements, such as St. John's wort, garlic tablets, and milk thistle, have recently been shown to interact with protease inhibitors, reducing their drug levels. Clinicians must also be aware of experimental protocols and when appropriate, make them available to their patients. As with any chronic disease, practitioners caring for HIV-infected patients will interact frequently with their patients' families and support networks. HIV disease is unique, however, in that in many cases, the patient's spouse, partner, friends, or family members may also be infected. Practitioners must recognize the importance of nontraditional families. Among gay couples, for example, in the event that the patient is unable to speak for himself, the patient's partner is usually a more appropriate decision- maker than the next of kin. However, for this role to be legally recognized, the partner must have been designated as the healthcare proxy or durable power of attorney for health. Patients should be encouraged as early as possible in the course of their disease to make their wishes known to their physician and family regarding:  their proxy for healthcare decisions;  wishes regarding terminal care and the aggressiveness with which it should be approached; and,  the disposition of their property following their death. Whenever possible, patients wishes should be formalized with the legal arrangements appropriate to their particular state. Although issues of death and dying are not unique to HIV care, they play a more prominent role than in many other fields of medicine. Although HAART has transformed HIV infection from an inevitably terminal disease to a chronic, manageable condition, the diagnosis of HIV infection still causes most patients to confront their mortality, and many will want to discuss their concerns with their primary care provider. Patients may ask direct questions concerning their prognosis and life expectancy, about what to expect as their disease becomes more advanced, or even about suicide and euthanasia. For many patients, these discussions with their healthcare provider are both informative and reassuring. Practitioners who are comfortable discussing death and dying openly can learn about their patients' fears and misconceptions. These

Florida Heart CPR* HIV Initial Treatment 23 discussions will help the clinician plan with the patient treatment strategies as the disease progresses. Ultimately, the practitioner must help the patient and family to acknowledge the inevitability of death, and at some point, the futility of further aggressive intervention. Quality-of-life issues play an important role in the care of HIV- infected patients and become increasingly important in patients with very advanced disease. For example, in some cases the diminishing benefits of continued antiretroviral therapy in patients with advanced disease may no longer outweigh the impaired quality of life associated with treatment-associated adverse reactions, and therapeutic efforts may be better directed at the prevention or suppression of opportunistic infections. Eventually, the manner of death must be viewed as an important quality-of-life issue, and the assurance that the patient will die without pain or unwanted intervention becomes the overriding concern. Finally, one of the most important roles of the clinician caring for HIV-infected individuals is to instill and encourage a sense of hope. In the last decade, enormous strides have been made in our ability to treat HIV infection. Furthermore, new developments in basic science research and drug development suggest that we will continue to be able to offer new, improved therapies to our patients in the coming years. Some HIV-infected individuals continue to embrace the more pessimistic or nihilistic attitude that was common before the advent of HAART. They may base this attitude on outdated information or on experience with friends who died before the availability of such therapy, or they may be legitimately concerned about the possibility of developing drug toxicity. A crucial element in the process of educating patients is to help them understand the enormous benefits associated with treatment of their HIV infection. Now that antiretroviral therapy is so effective, adherence has never been a more important issue. To derive the full benefit from their therapy, patients must fully understand the benefits of treatment and the risks associated with nonadherence. Outpatient care settings must develop a comprehensive and consistent plan for supporting and evaluating patient adherence.

Case History (continued) Laboratory data obtained on the patient's first visit included confirmatory ELISA and Western blot, which were both reactive. Absolute CD4+ cell count was 160 cells/mm3 (12%). The white blood cell count was 4000 cells/mm3, and the hematocrit was 34%. Platelet count was normal. Chemistries were normal except for mild elevations of the transaminases. Quantitative HIV RNA was 55,000 copies/mL. VDRL and anti- Toxoplasma IgG were negative. Anti-varicella IgG, anti-CMV IgG, and anti-HBc were positive. G-6-PD level was normal. PPD skin test was negative. Chest radiograph showed resolution of pneumonia. Pap smear revealed CIN 1. She was reported as having AIDS by CD4+ cell count criteria to the local health department. The patient returned 2 weeks after the initial visit. She reported that while she was anxious about what her test results would show, her sleep had improved and she was able to function better at work. The patient was attending counseling sessions and her support group, which she felt were worthwhile. She reported no new medical complaints. She was informed of her test results. She was told that her viral load was moderately elevated at 55,000 copies/mL, and that her CD4+ cell count, at 160 cells/mm3, indicated

Florida Heart CPR* HIV Initial Treatment 24 moderate immunosuppression. Both results indicated a need for antiretroviral therapy. After a discussion of the various options for antiretroviral therapy, the patient agreed to take combination therapy with 2 nucleoside analogues and a nonnucleoside reverse transcriptase inhibitor. The side effects of the drugs and the importance of strict compliance were discussed, and she was given pamphlets on each of the drugs. Pneumocystis prophylaxis and immunizations were deferred because of the expectation that her CD4+ cell count would increase with therapy. She was given an appointment to return for a nursing visit in 2 weeks to assess her ability to tolerate the medications and was scheduled for repeat laboratory testing in 4 weeks (CBC, chemistry panel, CD4+ cell count, HIV RNA), with a follow-up visit with the clinician 1 week later. The patient was also referred to a gynecologist for colposcopy.

References 1. Mylonakis E, Paliou M, Lally M, Flanigan TP, Rich JD. Laboratory testing for infection with the human immunodeficiency virus: Established and novel approaches. Am J Med. 2000;109:568-576. 2. CDC. Interpretation and use of the Western blot assay for serodiagnosis of human immunodeficiency virus type 1 infections. MMWR. 1989;38:1-7. 3. Vanhems P, Allard R, Cooper DA, et al. Acute human immunodeficiency virus type 1 disease as a mononucleosis-like illness: is the diagnosis too restrictive. Clin Infect Dis. 1997;24:965-970. 4. Daar ES. Virology and immunology of acute HIV type 1 infection. AIDS Res Human Retroviruses. 1998;14:S229-S234. 5. Daar ES, Little SJ, Pitt J, et al, and the Los Angeles County Primary HIV Infection Recruitment Network. Diagnosing primary HIV infection. Ann Intern Med. 2001;134:25-29. 6. Rosenberg ES, Altfeld M, Poon SH, et al. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000; 407:523-526. 7. Little SJ, Routy JP, Daar ES, et al. Antiretroviral drug susceptibility and response to initial therapy among recently HIV-infected subjects in North America. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4-8, 2001; Chicago, Illinois. Abstract 756. 8. US Dept of Health and Human Services and Henry J. Kaiser Family Foundation. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Published at: http://www.hivatis.org/. February 4, 2002. Accessed April 10, 2002. 9. Hermans P, Kabeya K, Van Wanzeele F, et al. Successful interruption of antiretroviral therapy (ARVT) in patients with primary HIV infection (PHI). Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 290.

10. CDC. 1998 Guidelines for the treatment of sexually transmitted diseases. MMWR. 1998;47(RR-1):1-118. 11. CDC. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR. 1998;47(RR-20);1-51. 12. USPHS/IDSA Prevention of Opportunistic Infections Working Group. 2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. Published at: http://www.hivatis.org/trtgdlns.html#Opportunistic. November 28, 2001. Accessed April 10, 2002. 13. Hirsch MS, Brun-Vézinet F, D'Aquila RT, et al. Antiretroviral drug resistance testing in adult HIV-1 infection. Recommendations of an International AIDS Society-USA panel. JAMA. 2000;283:2417-2426. 14. CDC. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR. 1992; 41(RR-17):1-19. 15. Kitahata MM, Koepsell TD, Deyo RA, Maxwell CL, Dodge WT, Wagner EH. Physicians' experience with the acquired immunodeficiency syndrome as a factor in patients' survival. N Engl J Med. 1996;334:701-707. 16. Carpenter CCJ, Cooper DA, Fischl MA, et al. Antiretroviral therapy in adults: updated recommendations of the International AIDS Society - USA Panel. JAMA. 2000;283:381-390. 17. CDC. General Recommendations on Immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR Recomm Rep. 2002;51(RR02):1- 36.

Florida Heart CPR* HIV Patient Initial Treatment Assessment 1. The outpatient evaluation should include a comprehensive intake history, physical exam, and laboratory tests that serve not only to stage the disease, but help the clinician to: plan follow-up care and immunizations, evaluate indications for OI prophylaxis, and a. determine the need for antiretroviral therapy b. review the patient's need for counseling, educational, and psychosocial support c. Both A and B d. Neither A nor B

2. The taking of a thorough history, including nonjudgmental but specific questioning about ______, has become even more important in identifying patients at risk for HIV infection. a. Sexual activity b. Drug use c. Sexual orientation d. Both A and B

3. Unfortunately, the diagnosis of HIV disease may still lead to a. social stigmatization b. loss of health insurance c. discrimination in employment and housing d. all of the above

4. Primary HIV infection, or the ______, refers to the symptom complex that occurs in 80% to 90% of infected patients following infection with HIV. a. Acute retroviral syndrome b. Chronic retroviral syndrome c. Acute viral infection d. Chronic viral infection

5. The typical time from exposure to onset of symptoms is 2 to 4 weeks, but rare cases have been reported in which symptoms are delayed by several months. While most symptomatic patients seek medical consultation, the diagnosis is often missed because the symptoms are ______. a. Not severe b. Embarrassing c. Nonspecific d. Not problematic

6. Clinicians evaluating HIV-infected patients for the first time should take a careful history, focusing specifically on common HIV-related symptoms, including fevers, weight loss, diarrhea, changes in neurologic function or mental status, and _____. a. Skin rashes or lesions b. Oral thrush or ulceration c. Night sweats d. All of the above

7. Physicians should a. Question patients about their medical history b. Encourage patients to inform their partners of their HIV status c. Question patients about behaviors that might lead to further transmission of HIV d. All of the above

8. Factors affecting the CD4+ cell count include: a. seasonal and diurnal variation b. intercurrent illness c. the use of corticosteroids d. all of the above

9. ______prevents the loss of immune function and allows for more effective immune reconstitution. a. Chemotherapy b. Immunotherapy c. Blood transfusion

d. Antiretroviral therapy

10. Both cellular and humoral immunity wane with the progression of HIV infection, and the ability to form specific antibodies after infection or immunization becomes progressively impaired. It is therefore important that vaccinations be given ______in the course of HIV infection. a. When symptoms appear b. As late as possible c. As early as possible d. Midway

Florida Heart CPR* HIV Initial Treatment