OPPORTUNISTIC INFECTIONS IN HIV DISEASE: DOWN BUT NOT OUT

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INFECTIONS IN THE COMPROMISED HOST

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OPPORTUNISTIC INFECTIONS IN HIV DISEASE: DOWN BUT NOT OUT Paul E. Sax, MD

The widespread use of combination antiretroviral therapy consisting of at least 3 active agents has completely transformed the management of human immunodeficiency virus (HIV) disease. For patients taking potent combination antiretroviral therapy (ART), beginning in 1996, there has been a dramatic decline in the incidence of AIDS-related opportunistic infections (01s) such as Pneumocystis carinii pneumonia (PCP), disseminated Mycobacterium avium complex (MAC), and invasive cytomegalovirus (CMV) disease.I7,29, 32, 41, 42, This decline occurred independent of the use of specific 0 1 prophylaxis. An additional remarkable effect of ART has been the resolution of certain complications for which previously no consistently effective therapy was given or available, such as progressive multifocal leukoencephalopathy,58 crypto~poridiosis,3~ azole-resistant candida esophagitis,63and Kaposi's sar~oma.'~ These data persuasively argue that the immune system recovery that occurs with potent antiretroviral therapy is of considerable qualitative, and not just quantitative (as measured by absolute CD4 cell count), nature. HIV-related opportunistic infections, therefore, now predominantly occur in the following clinical settings: (1) in patients not receiving antiretroviral therapy, either because of having previously undiagnosed HIV infection or because of their nonacceptance with prescribed treatment; (2) in the period after starting ART, because of lack of immune reconstitution or because of eliciting a previously absent inflammatory

From the Division of Infectious Diseases, HIV Program, Brigham and Women's Hospital; and Harvard Medical School, Boston, Massachusetts

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host response; or (3) because of failure of prescribed antiretroviral therapy caused by viral resistance. Surprisingly, despite high rates of virologic failure seen in clinical practice, rates of 01s remain low in those 33 Potential explanations for this apparent parawith virologic fai1~re.l~~ dox include the sustained elevations in CD4 cell counts despite virologic failure, attenuation of viral fitness that occurs with resistance mutations, and the fact that most patients with rebounding viral loads still have levels of viremia that are substantially below their treatment baseline. This article will focus on 01s as they occur in the context of presenting symptoms. It will focus on a symptom-based approach, with specific treatment strategies outlined as they relate to individual HIVrelated 01s outlined in the Appendix at the end of the article. RESPIRATORY ILLNESS HIV-related respiratory diseases are outlined in Table 1. Note that certain conditions may vary in incidence significantly based on local epidemiology or past patient residence. In the United States, the most notable examples are tuberculosis and endemic fungal infections (histoplasmosis, coccidiodomycosis, and blastomycosis). Tuberculosis (TB) is one of the most common HIV-related respiratory illnesses, particularly in urban areas; in other areas, HIV-related TB occurs infrequently except in immigrants or patients who are arriving from highly TB endemic areas. Important historical features in evaluating HIV-infected patients with respiratory symptoms include: The degree of HIV-related immunosuppression, based on clinical assessment or CD4 cell count, or both; for example, patients who present with thrush and a history of weight loss are often severely immunosuppressed, placing them at greater risk for diseases such as PCP

Table 1. CAUSES OF RESPIRATORY DISEASE IN PERSONS WITH HIV Very Common

Somewhat Common

Rare

Pneumocystis carinii S . pneumoniae H. influenzae MTB+

Pseudomonas aeruginosa Staphylococcus aureus Enteric GNR Histoplasma capsulatum C. neoformans Cytomeglovirus Kaposi's sarcoma Aspergillus spp. Pulmonary lymphoma Congestive heart failure

Nocardia asteroides Legionella spp. M . avium complex Toxoplasma gondii Crypfosporidium R. equii Primary pulmonary HTN Lymphocytic interstitial pneumonia (LIP)

*Incidence of tuberculosis as a cause of pulmonary disease is highly dependent on local rates of TB.

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The geographic and demographic group as a guide to whether a patient is at increased risk of TB or one of the endemic fungi Whether the patient is taking prophylaxis for a given 01; for example, acquired immune deficiency syndrome (AIDS) patients who are faithfully taking trimethoprim-sulfamethoxazole for PCP prophylaxis rarely experience a breakthrough case if they are adherent to this treatment7,50 The clinical course also helps narrow the differential diagnosis. The two most common conditions are bacterial pneumonia and PCP. HIV patients with bacterial pneumonia present in a similar fashion to those without HIV, complaining of an illness that occurred relatively acutely associated with chills, rigors, pleuritic chest pain, and sometimes purulent sputum. Patients ill over a period of weeks to months will more likely have PCP, tuberculosis, or a fungal i n f e ~ t i o nThe . ~ ~ radiographic appearance of the chest radiograph also can help focus the diagnosis. Commonly observed patterns are outlined in Table 2. Whereas diffuse interstitial infiltrates remain the most common radiographic appearance of PCP, patients receiving second-line agents for PCP prophylaxis-in

Table 2. RADIOGRAPHIC APPEARANCE OF RESPIRATORY DISEASE IN PERSONS WITH HIV Diffuse Infiltrates Common

PCP MTB (advanced HIV disease) Cryptococcosis Histoplasmosis

Uncommon

CMV HSV Influenza Coccidioides immitis (endemic areas) Toxoplasmosis Cryptosporidiosis MAC CHF LIP (mainly children, rare in adults)

Nodules or Masses Common Uncommon MTB Other atypical mycobacteria MAC Toxoplasmosis Cryptococcosis Other lung neoplasms Histoplasmosis Nocardia Aspergillosis PCP Kaposi's sarcoma Pulmonary lymphoma Focal Infiltrates with or without Cavitation Common Uncommon Pyogenic bacterial pneumonia R. equi MTB Nocardia

Legionella MAC PCP Aspergillosis

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particular aerosolized pentamidine-may have atypical radiographic presentations of PCP. These include apical infiltrates, numerous smallwalled cysts, pleural effusions, pneumothorax, or single or multiple nodules. The diagnostic approach to a patient with HIV-related respiratory disease should begin with relatively noninvasive methods of obtaining a definitive diagnosis. Useful testing includes a complete blood count (CBC) with differential, a serum lactate dehydrogenase (LDH) (elevated in most HIV-related PCP requiring hospitalization), two sets of blood cultures (particularly useful for diagnosis of invasive pneumococcal disease), an oxygen saturation or arterial blood gas, and an induced sputum sample for routing culture and immunofluorescence staining for Pneumocystis curinii. The sensitivity of the induced sputum for PCP diagnosis varies considerably based on the experience of the laboratory performing the test. In the author’s institution, where immunofluorescence staining on induced sputum sample has been performed since 1990, the sensitivity of the test for patients able to comply with the induced sputum procedure is approximately 90%. In sites where this technique is not regularly performed, it is generally more reliable to proceed rapidly to a bronchoscopy with lavage (BAL), since HIV-related PCP is associated with high organism burdens making BAL nearly 100% sensitive in this setting. Potential exceptions to this rule are those patients who are receiving aerosolized pentamidine, because they may have peripheral or pleural disease with relatively low organism burdens.

Pneumocystis carinii Pneumonia

Specifics of treatment recommendations for PCP are outlined in the Appendix. Several questions related to PCP treatment commonly arise:

When should adjunctive steroids be used? It is not uncommon for respiratory symptoms to worsen somewhat in the first several days of treatment. This may be caused by an increased inflammatory response of the host in response to dying organisms. Because of this deterioration, adjunctive steroids are recommended for patients who at baseline evaluation have moderate to severe PCP based on either having a room air p02 < 70 or a calculated A-a gradient > 35.8 Well-documented infectious complications of adjunctive steroids in this setting include an increased risk of thrush and herpes simplex infections. While other opportunistic infections-in particular CMV disease, TB, and disseminated fungal infections-remain a concern, studies have not clearly shown that adjunctive steroids for PCP increase the incidence of these conditions.22The strategy of adding “rescue” corticosteroids to patients being treated with PCP who then begin to deteriorate clinically is employed widely (including at the author’s center),

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although controlled clinical data supporting this practice are limited. How should adverse drug reactions be managed? Adverse drug reactions to trimethoprim-sulfamethoxazole are extremely common, occurring in from 25%-50% of patients. These include (in approximate frequency, most common first) rash, fever, gastrointestinal symptoms, hepatitis, hyperkalemia, leukopenia, and hemolytic anemia. Because of this high rate of adverse reactions, patients should be followed closely during the 21-day treatment period for both subjective symptoms and the development of laboratory abnormalities. Not surprisingly, it is common for patients to require a change in treatment to a second-line therapy (such as trimethoprim-dapsone or atovaquone) before treatment is finished. However, unless the adverse reaction was particularly severe (such as Stevens-Johnson syndrome or other life-threatening problem), the occurrence of an adverse reaction to trimethoprim-sulfamethoxazole during PCP treatment does not preclude the use of this agent for PCP prophylaxis, since the prophylaxis dose is usually one eighth the treatment dose or less. Should treatment be changed in a patient deteriorating on appropriate therapy? Some patients with severe HIV-related PCP will not respond to trimethoprim-sulfamethoxazole even after several days of treatment. If respiratory failure ensues, mechanical ventilation will be required. For patients who are being treated for severe PCP who do not appear to be improving after a week of therapy, switching to pentamidine is a reasonable option. Reasons for treatment failure in this setting are not clear; it may be related to the underlying severity of the pneumonia or the patient’s immune defects, or possibly pre-existing resistance of P. carinii to sulfonamides caused by mutations of the dihydropteroate synthase gene, although data are conflicting in this regard.28,31 It should be emphasized, however, that there are no prospective data to confirm that switching to pentamidine is more effective than continuing trimethoprim-sulfamethoxazole and other supportive care, and pentamidine treatment also is associated with high rates of adverse reactions. These include nausea, infusionrelated hypotension, hypoglycemia, hypocalcemia, renal failure, and pancreatitis. Should PCP ever be treated empirically? Because treatment of PCP is associated with high rates of adverse reactions, we generally advocate trying to make a definitive diagnosis over treating empirically. Empiric treatment can be considered, however, in the following circumstances: (1) typical clinical and radiographic presentation; (2) mild disease, usually amenable to outpatient therapy; (3)a patient not receiving trimethoprim-sulfamethoxazole as prophylaxis. What should be done about antiretroviral therapy? In general, patients receiving antiretroviral therapy at the time when they develop PCP should have their treatment continued, since inter-

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mittent antiretroviral therapy can lead to drug resistance. In newly diagnosed HIV-infected patients, or for those who have never taken antiretrovirals, the author favors finishing the treatment course of PCP prior to starting combination antiretroviral therapy. The major rationale behind this practice is that many of the adverse effects of PCP treatment-gastrointestinal distress, rash, leukopenia, hepatitis in particular-overlap with or may be additive to those of the antiviral agents. This practice of waiting until PCP is stabilized before starting antiretroviral therapy applies to nonPCP opportunistic infections, as well. It is worth emphasizing, however, that there may be individual cases-such as a prolonged hospital stay for PCP-associated pneumothorax-in which a patient may be able to benefit from starting antiretroviral therapy prior to discharge. Bacterial Pneumonia

Empiric treatment of bacterial pneumonia should target the most common HIV-associated pathogens, in particular Streptococcus pneumoniae and Huemophilus influenzae. HIV infected patients are at approximately 100-fold increased risk of invasive pneumococcal disease compared with the general population@,and this organism will account for 15%-22% of cases in which a pathogen is defined? Nontypable H. influenzae generally is the second most common cause of bacterial pneumonia. As the CD4 cell count falls, many patients will develop neutrophil dysfunction (both qualitative and quantitative) and be at increased risk of pneumonia secondary to Staphylococcus aureus, enteric gram-negative bacilli, and Pseudomonas aeruginosa. P. aeruginosa can cause a particularly aggressive invasive pneumonia, sometimes associated with bacteremia and frequent relapses after cessation of 53 It is seen most commonly in patients with severe CD4 cell count depletion (< 100 cells/mm3) who not only often have absolute neutrophil counts less than 1000, but also have antibiotic selection pressure exerted by trimethoprim-sulfamethoxazole and macrolide antibiotics taken for opportunistic infection prophylaxis. Based on the above information, treatment of bacterial pneumonia in HIV-infected patients should be either with a newer fluoroquinolone (levofloxacin, moxifloxacin, or gatifloxacin) or a cephalosporin (cefuroxime, cefotaxime, or ceftriaxone) with or without a macrolide. In patients with severe immunosuppression, a history of neutropenia, or prior infection with P. aeruginosa, empiric coverage of this organism should be included. While Legionella pneumophila is a relatively uncommon cause of community acquired pneumonia in HIV-infected patients compared with pyogenic organisms, the risk is significantly higher than among HIV-negative patients.39As a result, empiric coverage of legionella infection is not mandatory, but should be considered if the disease is relatively severe or if there is no response to more targeted treatment.

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CENTRAL NERVOUS SYSTEM DISEASE Causes of central nervous system disease in persons with HIV are outlined in Table 3. The initial diagnostic approach should consider the stage of immunosuppression, concomitant prophylaxis (in particular trimethoprim-sulfamethoxazole prophylaxis for PCP, which also protects against toxoplasmosis), and toxoplasmosis serology. A prior toxoplasmosis immunoglobulin value also is helpful if available because the vast majority of cases in the United States arise from reactivation of prior infection. By contrast, disseminated cryptococcal disease seems to be a consequence of recent infection, so a prior negative value does not help exclude the diagnosis. Central Nervous System Mass Lesions Certain conditions are commonly associated with focal brain lesions on CT scan or MRI. In patients with advanced HIV disease (CD4 cell counts < 100 cells/mm3), the two most common diagnoses are toxoplasmosis and primary central nervous system (CNS) lymphoma. Toxoplasmosis typically causes multiple lesions, whereas lymphoma causes single lesions that often cross the midline. There is, however, tremendous overlap in the radiographic appearances of these diseases. A trial of empiric therapy for toxoplasmosis in all patients could be recommended in the past because of the high occurrence of to~oplasmosis.~~ This approach is no longer valid given the declining incidence of CNS toxoplasmosis secondary to primary prophylaxis and effective antiretroviral therapy.* As a result, the author recommends the following approach to patients with advanced HIV disease and focal brain lesions with contrast enhancement. 1. Toxoplasmosis seropositive and not receiving toxoplasmosis prophylaxis: Begin an empiric trial of antitoxoplasmosis therapy (see AppenTable 3. CAUSES OF CENTRAL NERVOUS SYSTEM DISEASE IN PERSONS WITH HIV Very Common

Somewhat Common

Rare

C. neoformans T. gondii* Adverse drug reaction Psychiatric Illness HIV PML* CNS lymphoma"

MTB CMV Bacterial brain abscess*

Nocardia asteraides' H. capsulatum C. immitis Aspergillus spp.* Listeria monocytogenes

*Generally characterized by focal lesions on MRI or CT scan.

vzv

HSV' Treponema pallidum Acanthamoeba spp.* T. cruzi

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dix). Clinical response is usually seen within 7 days (and often sooner), and radiographic response in 14 days. If on treatment there is clinical improvement, a followup head MRI is recommended after 2 weeks of treatment. By contrast, should there be clinical deterioration while receiving treatment, imaging should be expedited with a low threshold to moving to stereotactic brain biopsy. 2. Toxoplasmosis seronegative or receiving toxoplasmosis prophylaxis or

lesions atypical radiographicalzy for toxoplasmosis (single, crosses midline, periventricular): Proceed with alternative diagnostic strategies (cerebrospinal fluid [CSF] examination or stereotactic brain biopsy) as discussed later in the article. Stereotactic brain biopsy can be done with safety comparable to those without AIDS and with a high diagnostic yield. In a series of 250 biopsies done over a 14-year period, one group found pathologically abnormal tissue in 246 (98%) of the procedures, and 16 patients (6%) had more than 1 diagn0sis.2~ Importantly, in one third of cases, the tissue diagnosis differed from the preoperative clinical diagnosis. Although the most common diagnoses found in this series were toxoplasmosis (15%) and lymphoma (33%),a wide variety of other infectious and neoplastic conditions were found, including progressive multifocal leukoencephalopathy (PML, 30%), primary H N encephalitis (lo"/.),and tumors not ordinarily associated with AIDS (3%). There has been increasing interest in the use of less invasive testing for the diagnosis of HN-related CNS disease, despite the relative safety of stereotactic brain biopsy. Experimental approaches include cerebrospinal fluid polymerase chain reaction (PCR) testing for a variety of infectious agents, including toxoplasmosis, CMV, JC virus (etiology of PML), Epstein-Barr virus (etiology of primary CNS lymphoma). The reported sensitivity and specificity of these tests vary widely,'l, but they may be useful in settings in which brain biopsy is not possible because of comorbid conditions or available resources. Nuclear medicine imaging, especially thallium-SPECT scans (in which lymphomas typically show increased tracer activity) also have been investigated, with varying degrees of predictive value.35,55 Overall, however, the results of nuclear imaging should not be used for making a definitive diagnosis without including all of the other clinical, laboratory, and radiographic data. For example, CSF PCR studies plus thallium-SPECT may improve the diagnostic precision of noninvasive testing: especially in the setting of a positive CSF sample for Epstein Barr virus (EBV) and a lesion on thallium-SPECT that shows increased thallium uptake. For patients who have focal abnormalities on MRI or CT that do not enhance with contrast administration, the most common diagnoses are primary H N encephalopathy, PML, and CMV infection, although the last of these often causes periventricular enhancement. When performing a CSF examination on a patient with HIV, the author recommends the following tests be done routinely: (1) opening

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pressure; (2) cell count, differential; glucose and protein; (3) Gram stain, routine cultures; (4) india ink, fungal culture, and CSF cryptococcal antigen; and (5) if from an endemic area or with relevant exposure history, mycobacterial stain and culture. The author also recommends that an additional 5 mL of fluid be obtained and held for further studies, especially PCR for JC virus, CMV, and EBV, should the diagnosis remain unclear after the first set of testing and these alternate diagnoses still be under consideration. Cerebrospinal fluid cytology has a low sensitivity for the diagnosis of primary CNS lymphoma, but can be helpful with high-grade peripheral Burkitt-type lymphomas that can spread to the meninges. Cryptococcal Meningitis The diagnosis of cryptococcal meningitis can be essentially ruled out with a negative serum cryptococcal antigen because the sensitivity If the antigen is positive, of this test in AIDS patients approaches however, then proceeding with a CSF examination is critical to measure opening pressure and other parameters. The medical management of cryptococcal meningitis involves initial therapy with amphotericin with or without flucytosine for 2 weeks, followed by lifelong maintenance therapy with fluconazole. With a slow clinical response to treatment, the author usually lengthens the course of amphotericin because comparative trials of acute management of cryptococcal meningitis suggest that amphotericin is preferable initially.49Should renal insufficiency or other adverse reactions preclude the use of amphotericin B, lipid formulations may be substituted; the author generally uses AmBisome at 4 mg/kg/ day. Should renal insufficiency or other adverse reactions preclude the use of amphotericin B, AmBisome at 4-6 mg/kg/day may be substih ~ t e dAdding .~~ flucytosine seems to improve the microbiologic response to treatment, and also possibly reduce the risk of relapse59;however, the drug can cause bone marrow suppression and gastrointestinal toxicity. The author’s approach is to start flucytosine in all patients, and have a low threshold for discontinuing it should toxicity ensue. A critical component of cryptococcal meningitis management is control of raised intracranial In a recent study of AIDS-related cryptococcal meningitis, elevation in pressure to >250 mm H,O was seen in 119 out of 221 patients.25Compared to those with normal pressure, the patients with elevated pressure had higher titers of cryptococcal antigen and were more likely to have positive India ink smears and more severe clinical manifestations of the disease, including headache, meningismus, papilledema, hearing loss, and pathologic reflexes. In addition, elevated baseline opening pressure was clearly associated with shortened longterm survival. In the initial CSF examination, sufficient CSF should be removed to bring the closing pressure down to less than 200 mm H,O or 50% of the initial pressure. For followup of raised pressure, options include repeated daily lumbar punctures until the pressure is stable,

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placement of a lumbar drain, or ventriculoperitoneal shunting?' Adjunctive corticosteroids are not recommended because of the high fungal burden and the paucity of inflammatory response typically seen in AIDS-related cryptococcosis, and the known deleterious effects these agents have on the prognosis in non-HIV-related cryptococcal disease. GASTROINTESTINAL DISEASE

HIV-infected patients commonly experience a wide variety of gastrointestinal symptoms, including diarrhea, nausea, vomiting, abdominal pain, and dysphagia. These could be related to active opportunistic infections or adverse effects of antiretroviral agents. A list of some of the common causes of diarrheal disease is outlined in Table 4. Important exposure history to elicit includes new antiretroviral agents, sexual activity, travel, and antibiotic use. Qualitative features of the diarrhea can help somewhat to narrow the diagnostic possibilities, although microbiologic studies will always be needed to confirm the suspected diagnosis. Crampy abdominal pain, bloating, and nausea suggest small bowel disease, as is common in protozoal infections (cryptosporidia, microsporidia, isospora, giardia, and cyclospora), and MAC. High-volume, watery diarrhea with weight loss and electrolyte disturbance is most characteristic of cryptosporidiosis, especially in association with advanced HIV disease. By contrast, bloody stools with abdominal cramping and fever would be more characteristic of an invasive bacterial pathogen, Clostridiurn dzfficile, or CMV colitis. The diagnostic approach to HIV-infected patients with diarrhea should begin by assessing a patient's immune status, exposure history (sexual, travel, medications), and characterization of the diarrhea and other associated symptoms. A stool sample for culture, C. difficile toxin, and ova and parasites (including special stains for the protozoal pathogens cryptosporidia, microsporidia, and cyclospora) should be obtained. If these studies are negative, and the diarrhea persists and is not clearly related to medications, referral to a gastroenterologist for endoscopic studies (esophagogastroduodenoscopyor flexible sigmoidoscopy or both) should be done promptly, especially if the patient is highly immunosuppressed (CD4 <200/mm3), losing weight, or has constitutional symp-

Table 4. CAUSES OF DIARRHEAL DISEASE IN PERSONS WITH HIV Very Common

CMV C. dificile Salmonella M . avium complex Giardia Protease inhibitors (esp. nelfinavir, ritonavir, lopinavir/ritonavir)

Somewhat Common

Shigella Campylobacter Microsporum Cyptosporidium Isospora Cyclospora

Rare

Amebiasis S. sterocoralis GI lymphoma Kaposi's sarcoma Enteroaggregative E . coli

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toms. In the absence of inflammatory diarrhea or colitis, symptomatic therapy with loperamide or other antimotility agents should be given. Certain other gastrointestinal pathogens and processes in HIV disease deserve special mention. Patients with HIV may experience gastroenteritis and bacteremia secondary to nontyphoidal Salmonella strains that can recur multiple times after therapy is d i s c ~ n t i n u e dThe . ~ ~ incidence of this problem has diminished, probably because of the concomitant administration of trimethoprim-sulfamethoxazole and other antibiotics for opportunistic infection prophylaxis, and also potentially because of antibacterial activity of zidovudine. While diarrhea from C. dijhcile has a high predilection for recurrence even in normal hosts, this is a particular problem in HIV-infected patients, who are sometimes receiving antimicrobial agents chronically for prophylaxis of other opportunistic infection^.^ The protozoal pathogens cryptosporidia, microsporidia, isospora, giardia, and cyclospora remain a relatively common cause of chronic diarrhea in patients with AIDS. Severity is highly dependent on underlying immune status. Treatment for cryptosporidiosis remains disappointing, with anecdotal responses to azithromycin, paromomycin, octreotide, and combination therapy sometimes reported.*" 56 The cornerstone of treatment for this recalcitrant pathogen, however, is augmentation of the immune response with antiretroviral therapy, which can induce a prolonged r e m i s ~ i o nFor . ~ ~the protozoal pathogen Isospova belli, a recent clinical trial found that 500 mg ciprofloxacin twice a day was nearly as effective as trimethoprim-sulfamethoxazole, and therefore is an alternative treatment for individuals intolerant to sulfonamides.60Treatment of microsporidiosis has been variably effective, using agents such as albendazole, atovaquone, and metronidazole. As with cryptosporidiosis, however, the most effective therapy is improving immune function through the use of antiretroviral agents.'O Cytomegalovirus can cause disease throughout the gastrointestinal tract, including oral and esophageal ulcers, gastritis, and (most commonly) colitis.18,a Cytomegalovirus colitis has a wide spectrum of clinical severity, but most typically causes fever, abdominal cramping, and sometimes bloody stools. Definitive diagnosis depends on finding the characteristic histopathology of CMV inclusions on biopsy. At the extreme severe end of the clinical spectrum is colonic perforation, and CMV colitis should be considered in any patient with AIDS who presents with an acute abdomen, especially if there is radiographic evidence of free intraperitoneal air. Many of the antiretroviral agents-in particular the protease inhibitors and didanosine (ddI)--can cause diarrhea that may be extremely inconvenient to patients. This is rarely so severe that weight loss ensues, and patients usually can pinpoint which of their medications is the culprit. Among the protease inhibitors, nelfinavir, ritonavir, and Iopinavir/ritonavir are most likely to cause diarrhea, though all of the drugs in this class can cause diarrhea and other gastrointestinal side effects.54 Given the high proportion of patients with diarrhea for which no infec-

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tious etiology can be found, a trial of an alternate antiretroviral regimen may be warranted if a substitution can be done safely from the perspective of virologic control. UNDIFFERENTIATED FEVER

Fever without localizing symptoms or signs is common in persons with HIV, and the cause largely depends on the clinical and laboratory stage of immunosuppression.57Patients with CD4 cell counts greater than 500/mm3 generally will have causes of fever similar to immunocompetent hosts. With counts between 200 mm3 and 500 mm3, the most common causes of fever will be respiratory bacterial infections (in particular, Streptococcus pneumoniue, H. influenzue) and tuberculosis, with complications of intravenous drug use also playing a major role depending on the risk behaviors of the patient. In advanced HIV disease, all of the above causes of fever are possible, and the more typical AIDSrelated opportunistic infections, which are outlined in Table 5. Disseminated Mycobacterium avium Complex (MAC) Infection and Immune Reconstitution Illnesses

In reviews conducted before the availability of potent antiretroviral therapy, disseminated Mycobacterium avium complex (MAC) was the most common cause of fever of unknown origin in patients with advanced AIDS?, 47, 52 Typical presenting symptoms of disseminated MAC include fever, night sweats, weight loss, and anorexia; diarrhea often is present. In such cases, diagnosis is usually established by blood culture using the lysis-centrifugation method or (less commonly) by bone marrow or liver biopsy. Recommended treatment of disseminated MAC is outlined in the Appendix. The typical presentation of MAC as a febrile, wasting illness has become markedly less common with the availability of potent antiretroviral therapy and chemoprophylactic regimens using rnacrolide~.~~, 45 Table 5. CAUSES OF UNDIFFERENTIATED FEVER IN PERSONS WITH HIV Very Common

M . avium complex M. tuberculosis' CMV Drug fever Sinusitis Central line infection Early l? carinii pneumonia HIV

Somewhat Common

C. neoformans H. capsulatum Endocarditis Lymphoma

Rare

Extrapulmonary P. carinii B. henselae C. immitis Mycobacterium kansasii l? marneffei Leishmania spp. T. gondii

*Incidenceof tuberculosis as a cause of fever is highly dependent on local rates of TB

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Instead, a more focal form of invasive MAC disease has emerged, in particular when patients with advanced HIV-related immunosuppression start potent antiretroviral therapy for the first time. This entity likely reflects a restoration of pathogen-specific immune responses to infections that are already present but not clinically detectable.I6 These ”immune reconstitution” illnesses to MAC most typically occur as lymphadenitis (mesenteric, cervical, thoracic), but also can mimic Pott’s disease with disease presenting in the spine.I4 The time of onset after starting antiretroviral therapy is usually within weeks to months, but they can occur as much as a year or later.I2 Generally biopsies show a granulomatous response that in the precombination-ART era was rarely seen in AIDS patients; the burden of organisms is highly variable, from sparsely seen to abundant. Immune reconstitution illnesses also have been described with tuberculosis, cytomegalovirus, hepatitis B and C, cryptococcosis, and histoplasmosis.16 As with the unusual focal disease without bacteremia in MAC, a common feature among these other infections is their atypical presentation. With CMV, for example, patients may present with vitritis, while with cryptococcal meningitis, there may be a marked cerebrospinal fluid pleocytosis or focal mass lesions. Such findings argue for increased immune responses underlying the pathogenesis of each of these conditions. The ideal treatment of immune reconstitution illnesses has not been established. In general, a strategy of continuing the antiretroviral therapy and starting specific antimicrobial treatment is suggested. As patients who develop immune reconstitution illnesses are generally severely immunosuppressed prior to starting antiretroviral therapy, the author believes every effort should be made to continue the antiviral therapy, even if this means administering a course of corticosteroids to reduce the inflammatory and febrile response. The author also has seen a patient resolve a MAC immune reconstitution illness without specific antimycobacterial therapy, presumably through the eventual development of sufficient immune function to control the infection through host defenses alone. Noninfectious Causes of Fever

Important noninfectious causes of fever include neoplasm and drug fever. Despite dramatic declines in the incidence of opportunistic infections with potent antiretroviral therapy, the rates of non-Hodgkin’s lymphoma appear to be relatively ~table.3~ As a result, lymphoma has assumed a larger proportion of the AIDS-related opportunistic infections over time, especially in those who are or once were severely immunosuppressed. Patients with HIV are highly predisposed to adverse drug reactions, and this complication becomes more common with advancing HIV disease.6The most common offenders are sulfonamide drugs and dapsone; rates of adverse drug reactions also are elevated to clindamycin, beta

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lactams, phenytoin, carbamazepine, thalidomide, and pentamidine. The non-nucleoside reverse transcriptase inhibitors nevirapine, delavirdine, and efavirenz also can cause febrile hypersensitivity reactions, both with and without rashes. Abacavir 's hypersensitivity reaction, occurring in approximately 3% of patients, usually is associated with fever and multisystem complaints. Patients who experience an abacavir hypersensitivity reaction should have the drug discontinued and never receive this agent again since continued therapy or re-challenge can be fatal. Diagnostic Evaluation of Fever

The diagnostic evaluation of patients with advanced HIV disease and fever should start with noninvasive tests and become more invasive if fevers p e r ~ i s tDepending .~ on the clinical status of the patient and his or her level of immunosuppression, one should have a low threshold for accelerating this workup to arrive at a definitive diagnosis. Obtaining a meticulous drug, travel, and other exposure history is essential. Physical examination should focus on skin rashes that may be evidence of disseminated fungal infections (cryptococcus may cause a characteristic molluscum-like rash), oral ulcerations (histoplasmosis, CMV), new or regional lymphadenopathy (lymphoma, immune reconstitution MAC), and hepatosplenomegaly (commonly seen in histoplasmosis, MAC, disseminated Pneumocystis carinii). Radiographs then should be done to corroborate these findings: abdominal CT scans frequently show mesenteric adenopathy in MAC disease, while CT of the chest often will show faint infiltrates due to early PCP that were not evident on plain films. The author has not found nuclear medicine studies useful, except as a means to stage aggressive non-Hodgkin's lymphomas. Routine blood cultures can diagnose endocarditis, salmonella bacteremia or an intravenous line infection; cultures using the lysis-centrifugation method are more sensitive for detection of disseminated MAC and histoplasmosis. Serum cryptococcal antigen, urine histoplasmosis antigen, and CMV antigenemia studies all may be appropriate if the above evaluation does not yield the diagnosis. The utility of liver biopsy and bone marrow biopsy in the evaluation of the HIV-infected patient with fever is highly variable, with reported . ~ ,23* 46, 47 In general, an elevated yields of biopsy ranging from ~ O - ~ O Y O 20, alkaline phosphatase level is a helpful predictor of whether a liver biopsy will be diagnostic. In both bone marrow biopsy and liver biopsy, MAC is the most common diagnosis, and often the diagnosis can be established noninvasively (though more slowly) through the use of isolated blood cultures. SUMMARY

Despite the marked improvement in patient survival and reduction in the incidence of HIV-related opportunistic infections with the intro-

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duction of potent, combination antiretroviral therapy, these infections remain a significant challenge in the management of HIV-infected patients. Ongoing issues that will require further study include a better characterization of immune reconstitution illnesses, other potential alterations in the natural history of opportunistic infections with antiretroviral therapy, and to what degree patients who experience failure of antiviral treatment become susceptible to various opportunistic processes.

References 1. Ammassari A, Scoppettuolo G, Murri R, et al: Changing disease patterns in focal brain lesion-causing disorders in AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 18:365, 1998 2. Antinori A, De Rossi G, Ammassari A, et a1 Value of combined approach with thallium-201 single-photon emission computed tomography and Epstein-Barr virus DNA polymerase chain reaction in CSF for the diagnosis of AIDS-related primary CNS lymphoma. J Clin Oncol 17554, 1999 3. Armstrong WS, Katz JT, Kazanjian P H Human immunodeficiency virus-associated fever of unknown origin: A study of 70 patients in the United States and review. Clin Infect Dis 28:341, 1999 4. Barbut F, Meynard JL, Guiguet M, et a1 Clostridium difficile-associated diarrhea in HIV-infected patients: Epidemiology and risk factors. J Acquir Immune Defic Syndr Hum Retrovirol 16:176, 1997 5. Bartlett JG: Pneumonia in the patient with HIV infection. Infect Dis Clin North Am 12807, 1998 6. Bayard PJ, Berger TG, Jacobson MA: Drug hypersensitivity reactions and human immunodeficiency virus disease. J Acquir Immune Defic Syndr 5:1237, 1992 7. Bozzette SA, Finkelstein DM, Spector SA, et al: A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group [see comments]. N Engl J Med 332693, 1995 8. Bozzette SA, Sattler FR, Chiu J, et a1 A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group [see comments]. N Engl J Med 323:1451, 1990 9. Cappell MS, Schwartz MS, Biempica L: Clinical utility of liver biopsy in patients with serum antibodies to the human immunodeficiency virus [see comments]. Am J Med 88:123, 1990 10. Carr A, Marriott D, Field A, et al: Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy [see comments]. Lancet 351256, 1998 11. Cinque P, Scarpellini P, Vago L, et al: Diagnosis of central nervous system complications in HIV-infected patients: Cerebrospinal fluid analysis by the polymerase chain reaction [editorial]. AIDS 11:1, 1997 12. Cinti SK, Kaul DR, Sax PE, et al: Recurrence of Mycobacterium avium infection in patients receiving highly active antiretroviral therapy and antimycobacterial agents. Clin Infect Dis 30:511, 2000 13. Cohn JA, McMeeking A, Cohen W, et a1 Evaluation of the policy of empiric treatment of suspected Toxoplasma encephalitis in patients with the acquired immunodeficiency syndrome. Am J Med 86:521, 1989 14. Currier JS, Williams PL, Koletar SL, et a1 Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4 + cell count: A randomized, double-blind, placebo-controlled trial. AIDS Clinical Trials Group 362 Study Team. Ann Intern Med 133:493, 2000

15. Deeks SG, Barbour JD, Martin JN, et al: Sustained CD4 + T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. J Infect Dis 181:946,2000 16. DeSimone JA, Pomerantz RJ, Babinchak TJ: Inflammatory reactions in HnT-1-infected persons after initiation of highly active antiretroviral therapy. Ann Intern Med 133:447, 2000 17. Detels R, Munoz A, McFarlane G, et al: Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators [see comments]. JAMA 280:1497, 1998 18. Dieterich DT, Rahmin M. Cytomegalovims colitis in AIDS Presentation in 44 patients and a review of the literature. J Acquir Immune Defic Syndr 4S29, 1991 19. Dupont C, Vasseur E, Beauchet A, et a1 Long-term efficacy on Kaposi's sarcoma of highly active antiretroviral therapy in a cohort of HIV-positive patients. CISIH 92. Centre &Information et de soins de 1'Immunodeficience humaine [in process citation]. AIDS 14:987,2000 20. Engels E, Marks PW, Kazanjian F: Usefulness of bone marrow examination in the evaluation of unexplained fevers in patients infected with human immunodeficiency virus. Clin Infect Dis 21:427, 1995 21. Fessler RD, Sobel J, Guyot L, et al: Management of elevated intracranial pressure in patients with cryptococcal meningitis. J Acquir Immune Defic Syndr Hum Retrovirol 17137,1998 22. Gallant JE, Chaisson RE, Moore R D The effect of adjunctive corticosteroids for the treatment of Pneumocystis curinii pneumonia on mortality and subsequent complications [see comments]. Chest 1141258, 1998 23. Garcia-Ordonez MA, Colmenero JD, Jimenez-Onate F, et al: Diagnostic usefulness of percutaneous liver biopsy in HIV-infected patients with fever of unknown origin. J Infect 38:94, 1999 24. Gildenberg PL, Gathe JC Jr, Kim JH: Stereotactic biopsy of cerebral lesions in AIDS. Clin Infect Dis 30:491, 2000 25. Graybill JR, Sobel J, Saag M, et al: Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis 30:47, 2000 26. Griffiths J K Treatment for AIDS-associated cryptosporidiosis [editorial; comment]. J Infect Dis 178915, 1998 27. Havlir DV, Dube MP, Sattler FR, et a1 Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group [see comments]. N Engl J Med 335:392, 1996 28. Helweg-Larsen J, Benfield TL, Eugen-Olsen J, et al: Effects of mutations in Pneumocystis curinii dihydropteroate synthase gene on outcome of AIDS-associated P. carinii pneumonia [see comments]. Lancet 3541347, 1999 29. Hogg RS, OShaughnessy MV, Gataric N, et al: Decline in deaths from AIDS caused by new antiretrovirals [letter]. Lancet 349:1294, 1997 30. Jacobson MA, Hahn SM, Gerberding JL, et al: Ciprofloxacin for Salmonella bacteremia in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 110:1027,1989 31. Kazanjian P, Armstrong W, Hossler PA, et al: Pneumocystis curinii mutations are associated with duration of sulfa or sulfone prophylaxis exposure in AIDS patients. J Infect Dis 182:551,2000 32. Ledergerber B, Egger M, Erard V, et al: AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: The Swiss HIV cohort study [see comments]. JAMA 2822220,1999 33. Ledergerber B, Egger M, Opravil M, et al: Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: A prospective cohort study. Swiss HIV Cohort Study. Lancet 3532363,1999 34. Ledergerber B, Telenti A, Egger M: Risk of HIV related Kaposi's sarcoma and nonHodgkin's lymphoma with potent antiretroviral therapy: Prospective cohort study. Swiss HIV Cohort Study. BMJ 319:23, 1999 35. Lee VW, Antonacci V, Tilak S, et al: Intracranial mass lesions: Sequential thallium and gallium scintigraphy in patients with AIDS. Radiology 211:507, 1999

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36. Leenders AC, Reiss P, Portegies P, et a1 Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS 113463, 1997 37. Maggi P, Larocca AM, Quarto M, et al: Effect of antiretroviral therapy on cryptosporidiosis and microsporidiosis in patients infected with human immunodeficiency virus type 1. Eur J Clin Microbiol Infect Dis 19:213, 2000 38. Manabe YC, Clark DP, Moore RD, et al: Cryptosporidiosis in patients with AIDS: Correlates of disease and survival. Clin Infect Dis 27536, 1998 39. Marston BJ, Lipman HB, Breiman W. Surveillance for Legionnaires’ disease: Risk factors for morbidity and mortality. Arch Intern Med 154:2417, 1994 40. Mendelson MH, Gurtman A, Szabo S, et al: Pseudomonas aeruginosa bacteremia in patients with AIDS. Clin Infect Dis 18886, 1994 41. Miller V, Staszewski S, Nisius G, et al: Risk of new AIDS diseases in people on triple therapy [letter]. Lancet 353:463, 1999 42. Mocroft A, Vella S, Benfield TL, et al: Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 352:1725, 1998 43. Mundy LM, Auwaerter PG, Oldach D, et al: Community-acquired pneumonia: Impact of immune status. Am J Respir Crit Care Med 1521309, 1995 44. Palella FJ Jr, Delaney KM, Moorman AC, et al: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators [see comments]. N Engl J Med 3382353, 1998 45. Pierce M, Crampton S, Henry D, et al: A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced acquired immunodeficiency syndrome [see comments]. N Engl J Med 335:384, 1996 46. Poles MA, Dieterich DT, Schwarz ED, et al: Liver biopsy findings in 501 patients infected with human immunodeficiency virus (HIV). J Acquir Immune Defic Syndr Hum Retrovirol 11:170, 1996 47. Prego V, Glatt AE, Roy V, et al: Comparative yield of blood culture for fungi and mycobacteria, liver biopsy, and bone marrow biopsy in the diagnosis of fever of undetermined origin in human immunodeficiency virus-infected patients [see comments]. Arch Intern Med 150:333, 1990 48. Saag MS, Graybill RJ, Larsen RA, et al: Practice guidelines for the management of cryptococcal disease: Infectious Diseases Society of America. Clin Infect Dis 30:710, 2000 49. Saag MS, Powderly WG, Cloud GA, et al: Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group [see comments]. N Engl J Med 326:83, 1992 50. Schneider MM, Hoepelman AI, Eeftinck Schattenkerk JK, et al: A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazoleas primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. The Dutch AIDS Treatment Group [see comments]. N Engl J Med 327:1836, 1992 51. Selwyn PA, Pumerantz AS, Durante A, et al: Clinical predictors of Pneumocystis carinii pneumonia, bacterial pneumonia and tuberculosis in HIV-infected patients. AIDS 12:885, 1998 52. Sepkowitz KA, Telzak EE, Carrow M, et al: Fever among outpatients with advanced human immunodeficiency virus infection. Arch Intern Med 153:1909, 1993 53. Shepp DH, Tang IT, Ramundo MB, et al: Serious Pseudomonas aeruginosa infection in AIDS. J Acquir Immune Defic Syndr 7823, 1994 54. Sherman DS, Fish DN: Management of protease inhibitor-associated diarrhea [in process citation]. Clin Infect Dis 30:908, 2000 55. Skiest DJ, Erdman W, Chang WE, et a1 SPECT thallium-201 combined with Toxoplasma serology for the presumptive diagnosis of focal central nervous system mass lesions in patients with AIDS [in process citation]. J Infect 40:274, 2000 56. Smith NH, Cron S, Valdez LM, et al: Combination drug therapy for cryptosporidiosis in AIDS [see comments]. J Infect Dis 178:900, 1998

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57. Sullivan M, Feinberg J, Bartlett JG: Fever in patients with HIV infection. Infect Dis Clin North Am 10:149, 1996 58. Tassie JM, Gasnault J, Bentata M, et al: Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. Clinical Epidemiology Group. French Hospital Database on HIV. AIDS 33:1881,1999 59. van der Horst CM, Saag MS, Cloud GA, et al: Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group [see comments]. N Engl J Med 337:15, 1997 60. Verdier RI, Fitzgerald DW, Johnson WD Jr, et al: Trimethoprim-sulfamethoxazole compared with ciprofloxacin for treatment and prophylaxis of Isospora belli and Cyclospora cayetanensis infection in HIV-infected patients. A randomized, controlled trial. Ann Intern Med 132885, 2000 61. Weber T: Cerebrospinal fluid analysis for the diagnosis of human immunodeficiency virus-related neurologic diseases. Semin Neurol 19:223, 1999 62. Whitley RJ, Jacobson MA, Friedberg DN, et a1 Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: Recommendations of an international panel. International AIDS Society-USA. Arch Intern Med 158:957, 1998 63. Zingman B S Resolution of refractory AIDS-related mucosal candidiasis after initiation of didanosine plus saquinavir [letter]. N Engl J Med 3341674, 1996

Address reprint requests to Paul E. Sax, MD Division of Infectious Diseases Brigham and Women’s Hospital 75 Francis Street Boston, MA 02115 e-mail: [email protected]

Fever, cough, dyspnea, often indolent in presentation. Physical exam usually normal. Chext x-ray quite variable; diffuse interstitial pattern most common. Elevated lactate dehydrogenase (LDH) and exercise desaturation highly suggestive of the diagnosis.

Pneurnocystis ctinii Pneumonia (PCP)

Clinical Presentation

X 21 days in 3-4 divided doses; oral therapy suitable for outpatient treatment, usually 2 doubiestrength tablets PO tid or qid

TMP 15 mg/kg/d + SMX 75 mg/kg/d PO or IV

First-Line Therapy

TMP 15-20 mg/kg/d PO divided tid (usually 300 mg tid) + dapsone 100 mg po/d X 21 days Pentamidine 4 mg/kg/d N x 21 days Clindamycin 600 mg IV q8h/300-450 mg PO q6h + primaquine 30 mg base po/day X 21 days Atovaquone 750 mg suspension PO with meal bid X 21 days Trimetrexate 45 mg/m2 IV/day + folinic acid 20 mg/m2 p o / N q6h

Alternative Treatment Regimens

Preferred TMP-SMX 1 DS PO s d or TMP-SMX 1 SS p o i d Alternative TMP-SMX 1 DS qd tiw Dapsone 100 mg qd Nebulized pentamidine 300 mg q month Atovaquone 1500 mg qd

Indication: CD4' count 4 0 0 or thrush or unexplained fever 2 2 weeks

Primary Prophylaxis

Appendix continued on follozuing page

TMP-SMX, TMP-dapsone and clindamycinprimaquine are equally effective in patients with mild to moderate PCP. Intolerance to TMP-SMX is noted in 25-50%, psimarily rash and fever. Patients with severe disease (PO, <70 mm Hg or A-a gradient >35 mm Hg) should receive corticosteroids (prednisone 40 mg PO bid X 5 days, then 40 mg qd X 5 days, then 20 mg qd to completion of treatment). Consider discontinuaton of primary prophylaxis in patients on antiretrovirai therapy when the CD4' count is >200 for more than 6 months.

Comments

Treatment and Prevention of Common HIV-Related Opportunistic Infections

APPENDIX

N

Oropharyngeal (Thrush) Pseudomembranous, white plaque on the tongue, palate or buccal mucosa which can be removed with scraping.

Candida

Encephalitis Wide spectrum of neurologic symptoms, including sensorimotor deficits, seizure, confusion, ataxia. Fever, headache common.

Toxoplasma

Clinical Presentation

Fluconazole 100 mg qd

Pyrimethamine 100-200 mg loading dose, then 50-100 mg/d + folinic acid 10 mg/d + sulfadiazine 4-8 g/d for at least 6 weeks

First-Line Therapy

Clotrimazole oral troches 10 mg 5 X / day Nystatin 500,000 units gargled 5 X /day Amphotericin B oral suspension 1-5 mL qid swish & swallow Itraconazole 200 mg qd tabs or 100 mg qd oral suspension

Pyrimethamine + folinic acid + clindamycin 900-1200 mg IV q6h or 300-450 mg po q6h for at least 6 weeks Pyrimethamine and folinic acid + one of azithromycin 1200-1500 mg/day 0’ clarithromycin 1 g bid or atovaquone 750 mg with food qid

Alternative Treatment Regimens

Not indicated

Indication: IgG antibody to Toxoplasma and CD4’ count 4 0 0 Preferred TMP-SMX 1 DS qd Alternative Dapsone 50 mg qd + pyrimethamine 50 mg qwk + leucovorin 25 mg qwk Atovaquone 1500 mg qd

Primary Prophylaxis

Treat until symptoms resolve (usually 7-14 days); improvement often seen within 2 4 4 8 hours. Fluconazole is superior to topical therapy in preventing relapses of thrush and treating candida esophagitis. Continuous treatment with fluconazole may lead to azole resistance.

After initial treatment, patients should receive lifelong suppressive therapy (secondary prophylaxis) with pyrimethamine 25-75 mg PO qd + foliic acid 10-25 mg qd + sulfadiazine 0.5-1.0 g PO qid; clindamycin 300450 mg qid an option for sulfadiazine intolerant Expect clinical improvement within 1 week and radiographic improvement within 2 weeks. Corticosteroids should be used for edema/ mass effect. Data on discontinuation of secondary prophylaxis in the context of antiretroviral therapy-induced increase in CD4 cell counts are too preliminary for a formal recommendation.

Comments

Treatment and Prevention of Common HIV-Related Opportunistic Infections (continued).

APPENDIX

Clotrimazole cream (1%) X 7-14 days 0 ' 100 mg qd X 7 days 0' 100 mg bid X 3 days or500mg x 1 FlGonazole 150 mg X 1 Ketoconazole 200 mg qd X 5-7 days 0 '200 mg bid X 3 days Fluconazole 400 mg qd X 6-10 weeks Itraconazole 200 mg tid x 3 days, then 200 mg bid Fluconazole 400 mg qd + flucytosine 100 m d k g qd Itraconazole 400 mg tab or 200 mg oral susp qd

Intravaginal miconazole suppository 200 mg X 3 days or cream (2%) X 7 days

Amphotericin B 0.7-1 mg/kg/d for 4-6 weeks, followed by oral fluconazole 200-400 mg/d Flucytosine 100 mg/kg/ day divided by 6 hours

Meningitis Often indolent onset of fever. headache, subtle cognitive effects. Occaasional meningeal signs and focal neurologic findings, though nonspecific presentation is the norm. Brain imaging often normal. CSF usually abnormal with markedly elevated opening pressure.

cyptococcus

White, cheesy vaginal discharge, or vulvar rash with or without itching and pain.

Vaginal

Itraconazole 100-200 mg bid or 100-200 mg oral suspension/day Amphotericin B 0.3-0.5 mg/kg/day IV ? 5flucytosine 100 mg/ kg/day x 5-7 days

Fluconazole 2 O M O O mg qd x 2-3 weeks

Esophageal Dysphagia and/or odynophagia, almost always in the setting of oropharyngeal thrush.

Routine prophylaxis against Cryptococcus is not currently recommended.

Not indicated

Not indicated

Amphotericin B preferred for initial treatment, but total dose prior to switch to fluconazole is arbitrary Reduction of elevated CSF pressure mandatory for successful treatment (see text). Discontinue flucytosine for GI, bone marrow toxicity. Fluconazole preferable to itraconazole for maintenance treatment. Lifelong maintenance treatment required; inadequate data for discontinuation of maintenance due to immune reconstitution. Appendix confinued on following page

Systemic therapy preferred over topical for esophagitis. Failure to improve on empiric therapy mandates endoscopy to look for other causes, especially herpesviruses, aphthous ulcers. Consider maintenance therapy in all patients with recurrent esophagitis, although this increases the probability of resistance. For recurrence, consider maintenance treatment with daily or weekly fluconazole.

I

I

_

Nomeningeal Cryptococcosis Pulmonarv SVmPtOms seen occasionally. Skin (molluscum-likelesions), joint, prostate involvement rare. Mycobacterium wium complex Disseminated MAC In patients with advanced disease (CD4’ <50), onset of fever, weight loss, fatigue, diarrhea suggest MAC disease. Anemia, elevated alkaline phosphatase occasionally seen. Focal disease (especially lymphadmitis) with negative isolator blood cultures can be seen after starting antiretroviral therapy as part of “immune reconstitution” illness.

Clinical Presentation

Amikacin 1C-15 mg/kg 4d Ciprofloxacin 500-750 mg bid

Clarithroymcin 500 mg bid ethambutol 15 mg/kg qd k rifabutin 300 mg qd

+

Itraconazole 200 mg tab bid or 100 mg oral susp qd X 610 weeks

Alternative Treatment Regimens

Fluconazole 200 mg bid x 6-10 weeks

First-Llne Therapy

Axithromycin 1200 mg qwk 0‘ Clarithromycin 500 mg bid

<50

Indication: CD4+ count

Primary Prophylaxis

Rifabutin dosing with PIS and NNRTIs: With indinavir, n e h v i r , or a m p ~ ~ v i r , use rifabutin 150 mg qd. With efavirenz, use rifabutin 450 mg qd. Severe constitutional or other symptoms secondary to immune reconstitution MAC may require treatment with corticosteroids. Consider discontinuation of primary prophylaxis in patients on HAART when the CD4’ count is 1100 for more than 6 months.

All patients with cryptococcosis should have lumbar puncture to exclude meningitis. Need for maintenance treatment is not established.

Comments

Treatment and Prevention of Common HIV-Related Opportunistic Infections (continued).

APPENDIX

I

~

I

~

~

Ganciclovir 5 mg/kg It' bid x 14-21 days

Patients not on PIS or NNRTIs: Isoniazid 300 mg qd Rifampin 600 mg qd Ethambutol 15-20 mg/kg 4d l'yrazinamide 25 mg/kg qd

~

Foscamet 60 mg/kg IV q8h or 90 mg/kg IV q12h x 14-21 days Intraocular ganciclovir (Vitrasert) q 6 mo % oral ganciclovir 1 g tid Cidofovir 5 mg/kg IV weekly X 2 then every other week Fomivirsen, 330 mg by intravitreal injection day 1 and 15, then monthly

Patients on PIS or NNRTIs: Isoniazid 300 mg qd Rifabutin 15M50 mg qd Ethambutol 15-20 mg/ kg qd l'yrazmamide 25 mg/kg qd

Routine prophylaxis against cytomegalovirus is not currently recommended.

Indication: TST reaction 2 5 mm 0' prior positive TST result without therapy 0'contact with case of active tuberculosis INH 300 mg qd X 9 months or INH 900 mg biw x 9 months or RIF 600 mg + PZA 20 mg/kg qd X 2 months

~

Oral ganciclovir should not be used as sole initial therapy; maintenance with oral ganciclovir is nearly as effective as IV ganciclovir, and should be avoided with lesions near the optic nerve or fovea. An ophthalmologist should be consulted. Role of chronic suppressive therapy for GI disease not determined. Lifelong maintenance therapy for CMV retinitis required with CD4' < 100; discontinuation may be indicated in patients with CD4' count >100-150 for >6 months.

Index of clinical suspicion must remain high in all HIV patients with unexplained febrile syndrome or pulmonary infiltrate. Use of protease inhibitors and NNRTIs precludes use of rifampin. Rifabutin dosing with PIS and NNRTIs: with indinavir, nelfinavir, or amprenavir, use rifabutin 150 mg qd; with efavirenz, use rifabutin 450 mg qd.

PIS = Protease inhibitors; NNRTIs = non-nucleoside reverse transcriptase inhibitors; INH = isoniazid; PZA = pyrazinamide.

-

Retinitis Blurred vision, scotomata and field cuts common. Disease is often bilateral, even when initial symptoms unilateral GI disease (Colitis, Esophagitis) Localizing smatoms, including odynophagia, abdominal pa& diarrhea

Cytomegalovirus

m.

Extrapulmonary TB More common in HIV than in non-

Pulmonary TB Can present atypically. Concomitant extrapulmonary and pulmonary disease is common, especially in advanced HIV disease. As a generalization, HIV patients with high CD4' cell counts are more likely to have a typical pulmonaq presentation. Patients with advanced HIV may have a diffuse interstitial pattern, hilar adenopathy, or even a normal chest film. Tuberculin skin testing (TST) negative in 40% of patients with disease.

Mycobacterium tuberculosis