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U.S. Centers for Disease Control and Prevention, National Institutes of Health and HIV Medicine Association/Infectious Diseases Society of America
Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents
Recommendations From CDC, the National Institutes of Health and the HIV Medicine Association/Infectious Diseases Society of America
December 17, 2004
Corresponding Author: Constance A. Benson, M.D., Antiviral Research Center, University of California, San Diego, 150 W. Washington St., Suite 100, San Diego, CA 92103. Telephone: 619-543-8080; Fax: 619-298-0177; e-mail: cbenson@ucsd.edu.
SummaryThe National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, and CDC have developed guidelines for treatment of opportunistic infections (OIs) among adults and adolescents infected with human immunodeficiency virus (HIV). These guidelines are intended for clinicians and other health-care providers who care for HIV-infected adults and adolescents, including pregnant women; they complement companion guidelines for treatment of OIs among HIV-infected children and previously published guidelines for prevention of OIs in these populations. They include evidence-based guidelines for treatment of 28 OIs caused by protozoa, bacteria, fungi, and viruses, including certain OIs endemic in other parts of the world but that might be observed in patients in the United States. Each OI section includes information on epidemiology, clinical manifestations, diagnosis, treatment recommendations, monitoring and adverse events, management of treatment failure, prevention of recurrence, and special considerations in pregnancy. Tables address drugs and doses, drug toxicities, drug interactions, adjustment of drug doses in persons with reduced renal function, and data about use of drugs in pregnant women.
IntroductionOpportunistic infections (OIs) continue to cause morbidity and mortality in patients with human immunodeficiency virus (HIV)-1 infection throughout the world. Potent combination antiretroviral therapy (ART) has reduced the incidence of OIs for certain patients with access to care. However, certain patients in the developed and developing world do not have access to care and have OIs. Other patients do not have a sustained response to antiretroviral agents for multiple reasons, including poor adherence, drug toxicities, drug interactions, or initial acquisition of a drug-resistant strain of HIV-1. Therefore, OIs will continue to cause substantial morbidity and mortality in patients with HIV-1 infection.The therapy of OIs has changed substantially during the AIDS epidemic. As more information about efficacy, toxicity, and interactions of the drugs to treat and prevent OIs has emerged, management strategies have evolved. New drugs have also become available that occupy important roles in our therapeutic armamentarium. These guidelines and the accompanying guidelines, Treating Opportunistic Infections Among HIV-Exposed and Infected Children, join two previous guidelines, The United States Public Health Service-Infectious Diseases Society of America Guidelines for the Prevention of Opportunistic Infections in Persons Infected with the Human Immunodeficiency Virus and The Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. The current guidelines share key features with their companion guidelines:
How to Use the Information in This ReportFor each of the diseases covered in this report, specific recommendations are provided. Recommendations are rated by the IDSA rating system. In this system, the letters A through E signify the strength of the recommendation for or against a treatment measure, and Roman numerals I through III indicate the quality of evidence supporting the recommendation (Box).
Effect of Antiretroviral Therapy on the Incidence and Management of OIsData from both randomized controlled trials and observational cohort studies document that antiretroviral therapy (ART) reduces the incidence of OIs and improves survival, independent of the use of antimicrobial prophylaxis, and reduces overall mortality among persons with HIV-1 infection (1-7). Potent ART does not replace the need for antimicrobial prophylaxis among patients with severe immune suppression. However, ART is the cornerstone of the overall strategy to reduce morbidity attributed to HIV-1-related infections and other HIV1-related processes.The clinical benefit of ART in reducing the risk for OIs over the short term has been best demonstrated for those with a CD4+ T lymphocyte count <200 cells/µL. Studies also support benefit in patients with CD4+ T lymphocyte counts >200 cells/µL, although the overall benefit of starting ART in this population is uncertain. Improvements in specific measures of immune function, including pathogen-specific immunity, have been well documented among patients who initiated ART at CD4+ T lymphocyte counts >200 cells/µL (8-10). Whether such measures correlate with clinical protection against infection or other HIV-1-related complications remains to be determined. In addition to preventing OIs, ART can lead to resolution or improvement of certain OIs, most notably for those where specific treatment is not available. Treatment of patients with ART in the setting of an OI also can result in an exuberant inflammatory reaction that might require the use of anti-inflammatory agents for clinical management. Finally, patients who receive potent ART can have atypical presentations of OIs either early after the initiation of ART or after prolonged treatment. Specific guidelines for the management of ART in the presence of acute OIs have not previously been developed. Two principal circumstances to consider include the initiation of ART in the setting of an acute OI, and the management of ART when an acute OI occurs in a patient who is already receiving ART. The management in each circumstance will vary depending on the degree of virologic and immunologic disease progression before initiation of ART and the virologic and immunologic benefit resulting from ART, the duration of HIV-1 disease before and since starting ART, and the potential for drug-drug interactions between the ART regimen and the treatment needed for the OI.
Initiation of ART in the Setting of an Acute OI (Treatment-Naive Patients)The benefits of ART in the setting of an acute OI include the improvement in immune function that would potentially contribute to faster resolution of the OI. The beneficial effect of initiating ART during an acute OI has been best demonstrated for OIs for which limited or no effective therapies are available. Reports detailing the resolution of cryptosporidiosis, microsporidiosis, progressive multifocal leukoencephalopathy (PML), and Kaposi sarcoma after the initiation of potent ART provide evidence that improving immune function can lead to improved outcome in the setting of an acute OI (11-14). Another benefit of immediate initiation of potent ART during an acute OI is the reduction in risk for a second OI.Arguments against the immediate initiation of ART concurrent with the diagnosis of an OI include drug toxicities including additive toxicities, distinguishing toxicities caused by antiretrovirals (ARVs) from toxicities related to drugs used to manage OIs, the potential for drug interactions between OI therapies and ART, and the potential for inflammatory immune reconstitution syndromes to complicate the management of the OI in this setting. Much simpler ART regimens are available for the treatment of HIV-1 disease, diminishing the argument to delay therapy for reasons of complexity. However, overlapping toxicities exist between OI treatments and ART regimens that can complicate the ability to identify drug specific toxicity. Drug interactions pose the biggest problem for the treatment of patients with tuberculosis (TB), but ART regimens compatible with TB treatment are available. Immune reconstitution syndromes have been described for mycobacterial infections (including disease caused by Mycobacterium avium complex [MAC] and Mycobacterium tuberculosis, Pneumocystis jiroveci pneumonia (PCP), toxoplasmosis, hepatitis B and hepatitis C viruses, cytomegalovirus (CMV) infection, varicella-zoster virus (VZV) infection, cryptococcal infection and PML (12,15-25). Immune reconstitution syndromes are characterized by fever and worsening of the clinical manifestations of the OI or new manifestations weeks after the initiation of ART. Determining the absence of recrudescence of the underlying OI and new drug toxicity or a new OI is important. If the syndrome does represent an immune reactivation syndrome, adding nonsteroidal anti-inflammatory agents or corticosteroids to alleviate the inflammatory reaction is appropriate. The inflammation might take weeks or months to subside. The largest number of published reports of immune reconstitution syndromes is among patients with TB disease. Patients can experience high fevers, worsening lymphadenopathy or transient-to-severe worsening of pulmonary infiltrates, and expanding central nervous system lesions (19,26,27). Such "paradoxical reactions" might be more common among HIV-1-infected patients with TB disease who were started on potent ART compared with those not started on ART and among patients with TB disease who were not HIV-1-infected (19). Reduction of HIV-1 RNA levels and marked increases in CD4+ T lymphocyte counts have been associated with the occurrence of paradoxical reactions in patients with TB disease or MAC (15,17,19, 26). Although the majority of reactions occur within the first few weeks after initiation of ART, some have occurred up to several months after the initiation of TB therapy or ART. No randomized controlled trials exist that demonstrate that initiating ART improves outcome for patients being treated with specific therapy for their acute OI. In addition, no data demonstrate that initiation of ART in the setting of an acute OI worsens the prognosis or treatment for that OI. Trials are underway to evaluate the most appropriate timing for initiation of ART in this context.
Management of Acute OIs in the Setting of ARTOIs that develop after patients have been started on potent ART can be categorized into three groups. The first group includes OIs that occur shortly after initiating ART (within 12 weeks). These cases are thought to be subclinical infections that have been unmasked by early immune reconstitution and are not considered to be early failure of ART (10,15,17,28-31).The second group includes reports of OIs occurring >12 weeks after initiation of ART among patients with suppressed HIV-1 RNA levels and sustained CD4+ T lymphocyte counts >200 cells/µL (32,33). Two cases of spinal MAC among patients with nadir CD4+ T lymphocyte counts <50 cells/µL who had sustained CD4+ T lymphocyte count increases to >200 cells/µL are examples. Determining whether these represent a form of immune reconstitution syndrome as opposed to incomplete immunity with the occurrence of a new OI is difficult. The presence of organisms by stain and culture suggests that, in either situation, specific therapy is indicated. The third group includes OIs that develop among patients who are experiencing virologic and immunologic failure while on potent ART. These represent clinical failure of ART.
When to Initiate ART in the Setting of an OINo consensus has been reached about the optimal time to start ART in the presence of a recently diagnosed OI. The decision to start potent ART should take into consideration the availability of effective therapy for the OI, the risk for drug interactions, overlapping drug toxicities, the risk for and consequences of the development of an inflammatory immune reconstitution syndrome, and the willingness and ability of patients to take and adhere to their regimens.In cases of cryptosporidiosis, microsporidiosis, PML, and Kaposi sarcoma, the early benefits of potent ART outweigh any increased risk, and potent ART should be started as soon as possible (AIII). In the setting of TB disease, MAC, PCP, and cryptococcal meningitis, awaiting a response to OI therapy is usually warranted before initiating ART (CIII). When an OI occurs within 12 weeks of starting ART, treatment for the OI should be started, and ART should be continued (AIII). When an OI occurs despite complete virologic suppression (i.e., late OI), therapy for the OI should be initiated, potent ART should be continued, and if the CD4+ T cell response to ART has been suboptimal, modification of the ART regimen may be considered (CIII). When an OI occurs in the setting of virologic failure, OI therapy should be started, antiretroviral resistance testing should be performed, and the ART regimen should be modified if possible to achieve better virologic control (AI).
Special Considerations During PregnancyNo large studies have been conducted on the epidemiology or manifestations of HIV-1-associated OIs among pregnant women. No data demonstrate that the spectrum differs from that among nonpregnant women with comparable CD4+ T lymphocyte counts. CD4+ T lymphocyte counts characteristically drop during pregnancy, probably because of dilutional effects of the increased plasma volume. CD4+ T lymphocyte percentages are generally more stable and should be used for determining degree of immune suppression during pregnancy (34-36).Physiologic changes occur during pregnancy that might impact the presentation of acute OIs and the considerations for implementing OI treatment or antiretroviral therapies. These changes include (37):
Pregnancy also impacts decisions about diagnostic testing. Fetal risk is not increased with cumulative radiation doses below 5 rads. Teratogenesis is observed in animals at doses of 100-200 rads. In humans, the primary risk associated with high dose radiation exposure is growth restriction, microcephaly, and developmental disabilities. The most vulnerable period is 8-15 menstrual weeks of gestation with minimal risk before 8 weeks and after 25 weeks. The apparent threshold for development of mental retardation is 20-40 rads, with risk increasing linearly with increasing exposures above this level. Among children, risk for carcinogenesis might be increased approximately one per 1,000 or less per rad of in utero radiation exposure (38). The majority of radiographic and nuclear medicine studies result in radiation exposure to the fetus that is much lower than the 5 rad recommended limit; therefore, pregnancy should not preclude usual diagnostic evaluation when an OI is suspected (Table 1) (38-40). Abdominal shielding should be used when feasible to further limit radiation exposure to the fetus. Experience with use of magnetic resonance imaging (MRI) in pregnancy is limited. Although no adverse fetal effects have been reported, the National Radiological Protection Board advises against use of MRI in the first trimester (38). Other procedures necessary for diagnosis of suspected OIs should be performed in pregnancy as indicated for nonpregnant patients. Pregnant women who are >20 weeks of gestation should not lie flat on their backs but should have the left hip elevated with a wedge to displace the uterus off of the great vessels and prevent supine hypotension. Adequate oxygenation should be maintained. Because of the serious nature of OIs among HIV-1-infected persons, diagnostic procedures and indicated therapy should not be withheld during pregnancy; the therapy with the least potential toxicity should be selected (Table 2). The predictive value of animal data for effects in humans is unclear. In addition, reproductive studies among animals usually include only one drug at a time, and HIV-1-infected pregnant women might be using multiple antiretroviral, OI, and other drugs concurrently. The potential for enhanced toxicity of combinations of drugs has not been evaluated. For pregnant women who have had an OI diagnosed and are not on ART, immediate initiation of ART with OI therapy should be encouraged (AIII) (41). Decisions about immediate versus delayed initiation of ART in pregnancy should take into account gestational age, maternal HIV-1 RNA levels and clinical condition, and potential toxicities and interactions between ART and OI drugs. Pregnant women with active OIs who receive drugs for which information about their use in pregnancy is limited should have additional evaluation of fetal growth and well-being. After first trimester exposure to agents of uncertain teratogenic potential, a detailed ultrasound examination at 18-20 weeks should be conducted to detect major anomalies, although the ultrasound will not detect all anomalies. For women who receive drugs throughout pregnancy or in the third trimester for which information about their use in pregnancy is limited, an ultrasound should be conducted every 4-6 weeks to assess fetal growth and fluid volume. Pregnant women in the third trimester should be instructed in daily fetal movement counting to detect decreased activity that might indicate fetal compromise. Weekly fetal nonstress testing should be initiated at 32 weeks of gestation unless indicated sooner based on clinical or ultrasound findings (42).
Disease Specific RecommendationsPneumocystis Jiroveci PneumoniaEpidemiologyPneumocystis jiroveci pneumonia (PCP) is caused by Pneumocystis jiroveci, a ubiquitous organism classified as a fungus but that shares biologic characteristics with protozoa. The taxonomy of the organism has been changed; Pneumocystis carinii now refers only to the pneumocystis that infects rodents, and Pneumocystis jiroveci refers to the distinct species that infects humans. The abbreviation PCP is still used to designate Pneumocystis pneumonia. Initial infection with P. jiroveci usually occurs in early childhood; two thirds of healthy children have antibody to P. jiroveci by age 2-4 years (43). PCP is a result either of reactivation of latent infection or new exposure to the organism. Rodent studies and case clusters among immunosuppressed patients indicate that spread among persons can occur by the airborne route. Disease probably occurs by new acquisition and by reactivation (44,45). Before the widespread use of primary PCP prophylaxis and effective ART, PCP occurred in 70%-80% of patients with AIDS (46). The course of treated PCP was associated with a mortality of 20%-40% in persons with profound immunosuppression. Approximately 90% of cases occurred among patients with CD4+ T lymphocyte counts of <200/µL. Other factors associated with a higher risk of PCP included CD4+ T lymphocyte percentage <15%, previous episodes of PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and higher plasma HIV-1 RNA (47,48). Incidence of PCP has declined substantially with widespread use of prophylaxis and effective ART; recent incidence rates among patients with AIDS in Western Europe and the U.S. are 2-3 cases per 100 person-years (49). The majority of cases occur among patients who are unaware of their HIV-1 infection or are not receiving ongoing HIV care (50) or among those with advanced immunosuppression (CD4+ T lymphocyte counts <100 cells/µL) (51). Clinical Manifestations The most common manifestations of PCP among HIV-1-infected persons are the subacute onset of progressive exertional dyspnea, fever, nonproductive cough, and chest discomfort that worsens over a period of days to weeks. The fulminant pneumonia observed among non-HIV-1-infected patients is less common (52,53). In mild cases, pulmonary examination is usually normal at rest. With exertion, tachypnea, tachycardia, and diffuse dry ("cellophane") rales might be observed (53). Oral thrush is a common co-infection. Fever is apparent in the majority of cases and might be the predominant symptom among some patients. Extrapulmonary disease is rare but can present in any organ and has been associated with use of aerosolized pentamidine prophylaxis. Hypoxemia, the most characteristic laboratory abnormality, might range from mild-to-moderate (room air arterial oxygen [pO2] of >70 mm/Hg or alveolar-arterial O2 difference, [A-a] DO2 <35 mm/Hg) to moderate-to-severe levels (pO2 <70 mm/Hg or [A-a] DO2 >35 mm/Hg). Oxygen desaturation with exercise is indicative of an abnormal A-a gradient but is nonspecific (54). Elevation of lactate dehydrogenase levels to >500 mg/dL is common but nonspecific (55). The chest radiograph typically demonstrates diffuse, bilateral, symmetrical interstitial infiltrates emanating from the hiLa in a butterfly pattern (53); however, patients with early disease might have a normal chest radiograph (56). In addition, atypical presentations with nodules, asymmetric disease, blebs and cysts, upper lobe localization, and pneumothorax occur. Cavitation or pleural effusion is uncommon in the absence of other pulmonary pathogens or malignancy, and the presence of a pleural effusion might indicate an alternative diagnosis. Approximately 13%-18% of patients with documented PCP have another concurrent cause of pulmonary dysfunction (e.g., TB, Kaposi sarcoma, or bacterial pneumonia) (57,58). Pneumothorax in a patient with HIV-1 infection should raise the suspicion of PCP (59,60). Thin-section computerized tomography (CT) demonstrating patchy ground-glass attenuation (61) or a gallium scan showing increased pulmonary uptake (62) increases the likelihood that a diagnostic study such as bronchoscopy would demonstrate PCP in patients with mild-to-moderate symptoms and a normal chest radiograph and might be useful in adjunctive studies. However, a negative thin-section CT scan does not rule out PCP. Diagnosis Because the clinical presentation, blood tests, or chest radiographs are not pathognomonic for PCP and the organism cannot be routinely cultivated, histopathologic demonstration of organisms in tissue, bronchoalveolar lavage fluid, or induced sputum (57,58,63,64) samples is required for a definitive diagnosis. Spontaneously expectorated sputum has low sensitivity and should not be submitted to the laboratory to diagnose PCP. Cresyl violet, Giemsa, Diff-Quik, and Wright stains detect both the cyst and trophozoite forms but do not stain the cyst wall; Gomori Methenamine Silver, Gram-Weigert and toluidine blue stain the cyst wall. Certain laboratories prefer direct immunofluorescent staining. Nucleic acid tests are being developed, but their use remains experimental (65,66). Previous studies of stained respiratory tract samples obtained by various methods indicate the following relative diagnostic sensitivities: induced sputum <50 to >90% (the sensitivity and specificity depends heavily on the quality of the specimens and the experience of the microbiologist or pathologist), bronchoscopy with bronchoalveolar lavage 90%-99%, transbronchial biopsy 95%-100%, and open lung biopsy 95%-100%. Because of the potential for certain processes to have similar clinical manifestations, a specific diagnosis of PCP should be sought rather than relying on a presumptive diagnosis. Treatment can be initiated before making a definitive diagnosis because organisms persist in clinical specimens for days or weeks after effective therapy is initiated (64). Treatment Recommendations Trimethoprim-sulfamethoxazole (TMP-SMX) is the treatment of choice (67,68) (AI). The dose must be adjusted for abnormal renal function. Multiple randomized clinical trials indicate that TMP-SMX is as effective as parenteral pentamidine and more effective than other regimens. Adding leucovorin to prevent myelosuppression during acute treatment is not recommended because of questionable efficacy and some evidence for a higher failure rate (69) (DII). Oral outpatient therapy of TMP-SMX is highly effective among patients with mild-to-moderate disease (68) (AI). Mutations associated with resistance to sulfa drugs have been documented, but their effect on clinical outcome is uncertain (70). Patients who have PCP despite TMP-SMX prophylaxis are usually effectively treated with standard doses of TMPSMX (BIII). Patients with documented PCP and moderate-to-severe disease, as defined by room air pO2 <70 mm/Hg or arterial-alveolar O2 gradient >35 mm/Hg, should receive corticosteroids as early as possible, and certainly within 72 hours after starting specific PCP therapy (71-75) (AI). If steroids are started at a later time, their benefits are unclear, although the majority of clinicians would use them in such circumstances for patients with severe disease (BIII). The preferred corticosteroid dose and regimen is prednisone 40 mg by mouth twice a day for days 1-5, 40 mg daily for days 6-10, and 20 mg daily for days 11-21 (72,73) (AI). Methylprednisolone at 75% of the respective prednisone dose can be used if parenteral administration is necessary. Alternative therapeutic regimens include 1) dapsone and TMP for mild-to-moderate disease (69,76) (BI) (this regimen may have similar efficacy and fewer side effects than TMPSMX but is less convenient because of the number of pills); 2) primaquine plus clindamycin (77-79) (BI) (this regimen is also effective in mild-to-moderate disease, and the clindamycin component can be administered intravenously for more severe cases; however, primaquine is only available orally; 3) intravenous pentamidine (80-82) (AI) (generally the drug of second choice for severe disease); 4) atovaquone suspension (67,83) (BI) (this is less effective than TMP-SMX for mild-to-moderate disease but has fewer side effects); and 5) trimetrexate with leucovorin (84) (BI) (this is less effective than TMP-SMX but can be used if the latter is not tolerated and an intravenous regimen is needed). Leucovorin must be continued 3 days after the last trimetrexate dose. The addition of dapsone, sulfamethoxazole, or sulfadiazine to trimetrexate might improve efficacy on the basis of the sequential enzyme blockade of folate metabolism, although no study data exist to confirm this (CIII). Aerosolized pentamidine should not be used for the treatment of PCP because of limited efficacy and more frequent relapse (82,85,86) (DI). The recommended duration of therapy for PCP is 21 days (52) (AII). The probability and rate of response to therapy depends on the agent used, number of previous episodes, severity of illness, degree of immunodeficiency, and timing of initiation of therapy. Although the overall prognosis of patients whose degree of hypoxemia requires intensive care unit (ICU) admission or mechanical ventilation remains poor, survival in up to 40% of patients requiring ventilatory support has been reported in recent years (87-89). Because long-term survival is possible for patients in whom ART is effective, certain patients with AIDS and severe PCP should be offered ICU admission or mechanical ventilation when appropriate (e.g., when they have reasonable functional status) (AII). Because of the potential for additive or synergistic toxicities associated with anti-PCP and antiretroviral therapies, certain health-care providers delay initiation of ART until after the completion of anti-PCP therapy, despite some suggestion of potential benefit for early ART (88) (CIII). An immune recovery inflammatory syndrome has been described for PCP (90) and might complicate the concurrent administration of anti-PCP treatment and ART. Monitoring and Adverse Events Careful monitoring during therapy is important to evaluate response to treatment and to detect toxicity as soon as possible. Follow-up after therapy includes assessment for early relapse, especially when therapy has been with an agent other than TMP-SMX or was shortened for toxicity. PCP prophylaxis should be initiated promptly and maintained until the CD4+ T lymphocyte count is >200 cells/µL. If PCP occurred at a CD4+ T lymphocyte count >200 cells/µL, maintaining PCP prophylaxis for life regardless of the CD4+ T cell response might be prudent; however, data about the most appropriate approach in this setting are limited. Adverse reaction rates among patients with AIDS are high for TMP-SMX (20%-85%) (67,68,76,78,80,81,84,91-93). Common adverse effects are rash (30%-55%) (including Stevens-Johnson syndrome), fever (30%-40%), leukopenia (30%-40%), thrombocytopenia (15%), azotemia (1%-5%), hepatitis (20%), and hyperkalemia. Supportive care for common adverse effects should be attempted before discontinuing TMP-SMX (AIII). Rashes can often be "treated through" with antihistamines, nausea can be controlled with antiemetics, and fever can be managed with antipyretics. The most common adverse effects of alternative therapies include methemoglobinemia and hemolysis with dapsone or primaquine (especially in those with G-6-PD deficiency), rash, and fever with dapsone (68,76); azotemia, pancreatitis, hypo- or hyperglycemia, leukopenia, fever, electrolyte abnormalities, and cardiac dysrhythmia with pentamidine (80-83); anemia, rash, fever, diarrhea, and methemoglobinemia with primaquine and clindamycin (68,77,78); headache, nausea, diarrhea, rash, fever, and transaminase elevations with atovaquone (67,91); and bone marrow suppression, fever, rash, and hepatitis with trimetrexate (84). Management of Treatment Failure Clinical failure is defined by the lack of improvement or worsening of respiratory function documented by arterial blood gases after at least 4-8 days of anti-PCP treatment. Treatment failure attributed to treatment-limiting toxicities occurs in up to one third of patients (69). Failure attributed to lack of drug efficacy occurs in approximately 10% of those with mild-to-moderate disease. Adding or switching to another regimen is the appropriate management for treatment-related toxicity (BII). No convincing clinical trials exist to base recommendations for the management of treatment failure attributed to lack of drug efficacy. It is important to wait at least 4-8 days before switching therapy for lack of clinical improvement (BIII). In the absence of corticosteroid therapy, early and reversible deterioration within the first 3-5 days of therapy is typical, probably because of the inflammatory response caused by antibiotic-induced lysis of organisms in the lung. Other concomitant infections must be excluded as a cause for such deterioration (57,58). Bronchoscopy with bronchoalveolar lavage should be strongly considered even if it was conducted before initiating therapy. If TMP-SMX has failed or must be avoided for toxicity in moderate-to-severe disease, the common practice is to use parenteral pentamidine, primaquine combined with clindamycin, or trimetrexate (with or without oral dapsone) plus leucovorin (78,80,84) (BII). For mild disease, atovaquone is a reasonable alternative (BII). Although one meta-analysis concluded that the combination of clindamycin and primaquine might be the most effective regimen for salvage therapy (79), no prospective clinical trials have evaluated the optimal approach to patients who fail therapy with TMP-SMX. Prevention of Recurrence Patients who have a history of PCP should be administered secondary prophylaxis (chronic maintenance therapy) for life with TMP-SMX unless immune reconstitution occurs as a result of ART (94) (AI). For patients who are intolerant of TMP-SMX, alternatives are dapsone, dapsone combined with pyrimethamine, atovaquone, or aerosolized pentamidine. Secondary prophylaxis should be discontinued for adult and adolescent patients whose CD4+ T lymphocyte cell count has increased from <200 cells/µL to >200 cells/µL for at least 3 months as a result of ART (94-97) (AI). Secondary prophylaxis should be re-introduced if the CD4+ T lymphocyte count decreases to <200 cells/µL (AIII) or if PCP recurs at a CD4+ T lymphocyte count of >200 cells/µL (CIII). Special Considerations During Pregnancy Diagnostic considerations during pregnancy are the same as for nonpregnant women. Indications for therapy are the same as for nonpregnant women. The preferred initial therapy during pregnancy is TMP-SMX, although alternate therapies can be used if patients are unable to tolerate or are unresponsive to TMP-SMX (98) (AI). Neonatal care providers should be informed of maternal sulfa or dapsone therapy if used near delivery because of the theoretical increased risk for hyperbilirubinemia and kernicterus (99). Pentamidine is embryotoxic but not teratogenic among rats and rabbits (100). Trimetrexate should not be used because of teratogenicity at low doses in multiple animal studies, fetopathy in humans associated with use of the biochemically similar agents methotrexate and aminopterin, and the potential negative effects on placental and fetal growth (101) (EIII). Adjunctive corticosteroid therapy should be used as indicated in nonpregnant adults (102-105) (AIII). Maternal fasting and postprandial glucose levels should be monitored closely when corticosteroids are used in the third trimester because the risk for glucose intolerance is increased. Rates of preterm labor and preterm delivery are increased with pneumonia during pregnancy. Pregnant women with pneumonia after 20 weeks of gestation should be monitored for evidence of contractions (BII).
Toxoplasma gondii EncephalitisToxoplasmic encephalitis (TE) is caused by the protozoan Toxoplasma gondii. Disease occurs almost exclusively because of reactivation of latent tissue cysts (106-109). Primary infection occasionally is associated with acute cerebral or disseminated disease. Seroprevalence varies substantially among different communities (e.g., approximately 15% in the United States and 50%-75% in certain European countries) (109,110). In the pre-ART era, for patients with advanced immunosuppression who were seropositive for T. gondii and not receiving prophylaxis with drugs active against T. gondii, the 12-month incidence of TE was approximately 33%. The incidence and associated mortality in Europe and the United States has decreased substantially with the initiation of ART and the broad use of prophylaxis regimens active against T. gondii (111-113).Clinical disease is rare among patients with CD4+ T lymphocyte counts >200 cells/µL. The greatest risk is among patients with a CD4+ T lymphocyte count <50 cells/µL (106-108). Primary infection occurs after eating undercooked meat containing tissue cysts or ingestion of oocysts that have been shed in cat feces and have sporulated in the environment (which requires at least 24 hours). No transmission of the organism occurs by person-to-person contact. Clinical Manifestations The most common clinical presentation of T. gondii infection among patients with AIDS is a focal encephalitis with headache, confusion, or motor weakness and fever (106-108). Physical examination might demonstrate focal neurological abnormalities, and in the absence of treatment, disease progression results in seizures, stupor, and coma. Retinochoroiditis, pneumonia, and evidence of other multifocal organ system involvement can be seen after dissemination of infection but are rare manifestations in this patient population. CT scan or MRI of the brain will typically show multiple contrast-enhancing lesions, often with associated edema (106,107,114-116). Positron emission tomography (PET) (115) or single-photon emission computed tomography (SPECT) scanning (116) might be helpful for distinguishing between TE and primary central nervous system (CNS) lymphoma, but no imaging technique is completely specific. Diagnosis HIV-1-infected patients with TE are almost uniformly seropositive for anti-toxoplasma IgG antibodies (106-108, 117). The absence of IgG antibody makes a diagnosis of toxoplasmosis unlikely but not impossible. Anti-toxoplasma IgM antibodies are usually absent. Quantitative antibody titers are not diagnostically useful. Definitive diagnosis of TE requires a compatible clinical syndrome; identification of one or more mass lesions by CT, MRI, or other radiographic testing; and detection of the organism in a clinical sample. For TE, this requires a brain biopsy, which is most commonly performed by a stereotactic CT-guided needle biopsy. Organisms are demonstrable with hematoxylin and eosin stains, though immunoperoxidase staining by experienced laboratories might increase sensitivity (118). Detection of T. gondii by polymerase chain reaction (PCR) in cerebrospinal fluid has produced disappointing results; although specificity is high (96%-100%), sensitivity is low (50%) and the results usually are negative once specific anti-toxoplasma therapy has been started (119,120). In the presence of neurologic disease, the differential diagnosis (121) includes CNS lymphoma, mycobacterial infection (especially TB), fungal infection (e.g. cryptococcosis), Chagas disease, bacterial abscess, and rarely PML, which can be distinguished on the basis of imaging studies (PML lesions typically involve white matter rather than gray matter, are noncontrast enhancing, and indicate no mass effect). Certain clinicians rely initially on an empiric diagnosis, which can be established as an objective response, on the basis of clinical and radiographic improvement, to specific anti-T. gondii therapy in the absence of a likely alternative diagnosis. Brain biopsy is reserved for patients failing to respond to specific therapy. Treatment Recommendations The initial therapy of choice consists of the combination of pyrimethamine plus sulfadiazine plus leucovorin (122-125) (AI). Pyrimethamine penetrates the brain parenchyma efficiently even in the absence of inflammation (126). Use of leucovorin prevents the hematologic toxicities associated with pyrimethamine therapy (127,128). The preferred alternative regimen for patients unable to tolerate or who fail to respond to first-line therapy is pyrimethamine plus clindamycin plus leucovorin (122,123) (AI). TMP-SMX was reported in a small (77 patient) randomized trial to be effective and better tolerated than pyrimethamine-sulfadiazine (129). On the basis of less in vitro activity and less experience with this regimen, pyrimethamine plus sulfadiazine with leucovorin is the preferred therapy (BI). For patients who cannot take an oral regimen, no well-studied options exist. No parenteral formulation of pyrimethamine exists; the only widely available parenteral sulfonamide is the sulfamethoxazole component of TMP-SMX. Therefore, certain specialists will treat severely ill patients requiring parenteral therapy initially with oral pyrimethamine plus parenteral TMP-SMX or parenteral clindamycin (CIII). At least three regimens have activity in the treatment of TE in at least two, nonrandomized, uncontrolled trials, although their relative efficacy compared with the previous regimens is unknown: 1) atovaquone (with meals or oral nutritional supplements) plus pyrimethamine plus leucovorin (130) (BII); 2) atovaquone combined with sulfadiazine or, for patients intolerant of both pyrimethamine and sulfadiazine, as a single agent (130) (BII) (if atovaquone is used alone, measuring plasma levels might be helpful given the high variability of absorption of the drug among different patients; plasma levels of >18.5 µg/mL are associated with an improved response rate) (131-133); and 3) azithromycin plus pyrimethamine plus leucovorin daily (134,135) (BII). The following regimens have been reported to have activity in the treatment of TE in small cohorts of patients or in case reports of one or a few patients: clarithromycin plus pyrimethamine (136) (CIII); 5-fluoro-uracil plus clindamycin (137) (CIII), dapsone plus pyrimethamine plus leucovorin (138) (CIII); and minocycline or doxycycline combined with either pyrimethamine plus leucovorin, sulfadiazine, or clarithromycin (139,140) (CIII). Although the clarithromycin dose used in the only published study was 1 g twice a day, doses >500 mg have been associated with increased mortality in HIV-1-infected patients treated for disseminated MAC. Doses >500 mg twice a day should not be used (DIII). Acute therapy should be continued for at least 6 weeks, if there is clinical and radiologic improvement (106-109) (BII). Longer courses might be appropriate if clinical or radiologic disease is extensive or response is incomplete at 6 weeks. Adjunctive corticosteroids (e.g. dexamethasone) should be administered when clinically indicated only for treatment of a mass effect associated with focal lesions or associated edema (BIII). Because of the potential immunosuppressive effects of corticosteroids, they should be discontinued as soon as clinically feasible. Patients receiving corticosteroids should be closely monitored for the development of other OIs, including cytomegalovirus retinitis and TB disease. Anticonvulsants should be administered to patients with a history of seizures (AIII), but should not be administered prophylactically to all patients (DIII). Anticonvulsants, if administered, should be continued at least through the period of acute therapy. Monitoring and Adverse Events Changes in antibody titers are not useful for monitoring responses to therapy. Patients should be routinely monitored for adverse events and clinical and radiologic improvement (AIII). Common pyrimethamine toxicities include rash, nausea, and bone-marrow suppression (neutropenia, anemia, and thrombocytopenia) that can often be reversed by increasing the dose of leucovorin to 50-100 mg/day administered in divided doses (CIII). Common sulfadiazine toxicities include rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, and crystalluria. Common clindamycin toxicities include fever, rash, nausea, diarrhea (including pseudomembranous colitis or diarrhea related to Clostridium difficile toxin), and hepatotoxicity. Common TMP-SMX toxicities include rash, fever, leukopenia, thrombocytopenia, and hepatotoxicity. Drug interactions between anticonvulsants and antiretroviral agents should be carefully evaluated and doses adjusted according to established guidelines. Management of Treatment Failure A brain biopsy, if not previously performed, should be strongly considered for patients who fail to respond to initial therapy (BII) as defined by clinical or radiologic deterioration during the first week despite adequate therapy or lack of clinical improvement within 2 weeks. For those who undergo brain biopsy and have confirmed histopathologic evidence of TE, a switch to an alternative regimen as previously described should be considered (BIII). Recurrence of disease during secondary maintenance therapy following an initial clinical and radiographic response is unusual if patients adhere to their regimen. Prevention of Recurrence Patients who have successfully completed a 6-week course of initial therapy for TE should be administered lifelong secondary prophylaxis (i.e., chronic maintenance therapy) (141-143) unless immune reconstitution occurs because of ART (AI). Adult and adolescent patients appear to be at low risk for recurrence of TE when they have successfully completed initial therapy for TE, remain asymptomatic with respect to signs and symptoms of TE, and have a sustained (i.e., >6 months) increase in their CD4+ T lymphocyte counts to >200 cells/µL on ART (144,145). The numbers of such patients who have been evaluated remain limited. On the basis of these observations and inference from more extensive data about safety of discontinuing secondary prophylaxis for other OIs during advanced HIV-1 disease, discontinuing chronic maintenance therapy among such patients is a reasonable consideration (CIII). Certain health-care providers would obtain an MRI of the brain as part of their evaluation to determine whether discontinuation of therapy is appropriate and might be reluctant to stop therapy if any mass lesion or contrast enhancement persists (CIII). Secondary prophylaxis should be started again if the CD4+ T lymphocyte count decreases to <200 cells/µL (AIII). Special Considerations During Pregnancy Documentation of maternal T. gondii serologic status should be obtained during pregnancy. Indications for treatment of T. gondii during pregnancy should be based on confirmed or suspected symptomatic disease in the mother. Pediatric care providers should be informed if the HIV-1-infected mother is seropositive for T. gondii infection to allow evaluation of the neonate for evidence of congenital infection. Pregnant HIV-1-infected women with suspected or confirmed primary T. gondii infection during pregnancy should be managed in consultation with a maternal-fetal medicine or other appropriate specialist (146) (BIII). Treatment should be the same as in nonpregnant adults (BIII). Although pyrimethamine has been associated with birth defects in animals, limited human data have not suggested an increased risk for defects and, therefore, it can be administered to pregnant women (147,148). Pediatric providers should be notified if sulfadiazine is continued until delivery because its use might increase the risk for neonatal hyperbilirubinemia and kernicterus (148). Although perinatal transmission of T. gondii normally occurs only with acute infection in the immunocompetent host, case reports have documented occurrences of transmission with reactivation of chronic infection in HIV-1-infected women with severe immunosuppression (147,149). Because the risk for transmission with chronic infection appears low, routine evaluation of the fetus for infection with amniocentesis or cordocentesis is not indicated. Detailed ultrasound examination of the fetus specifically evaluating for hydrocephalus, cerebral calcifications, and growth restriction should be done for HIV-1-infected women with suspected primary or symptomatic reactivation of T. gondii during pregnancy.
CryptosporidiosisEpidemiologyCryptosporidiosis is caused by Cryptosporidium species, a group of protozoan parasites that infect the small bowel mucosa, and in immunosuppressed persons, the large bowel and extraintestinal sites. Those at greatest risk for disease are patients with advanced immunosuppression (i.e., CD4+ T lymphocyte counts generally <100 cells/µL) (150). The three most common species infecting humans are C. hominis (formerly C. parvum genotype 1 or human genotype), C. parvum (formerly C. parvum genotype 2 or bovine genotype), and C. meleagridis. In addition, infections with C. canis, C. felis, C. muris, and Cryptosporidium pig genotype have been reported in immunocompromised patients. Preliminary analyses indicate that some zoonotic species might have a stronger association with chronic diarrhea than C. hominis. However, whether the different Cryptosporidium species are associated with differences in severity of disease or response to therapy is unknown. In developed countries with low rates of environmental contamination where potent ART is widely available, cryptosporidiosis occurs at an incidence rate of <1 per 100 person-years among persons with AIDS. Transmission occurs through ingestion of Cryptosporidium oocysts. C. hominis infects only humans, and C. parvum infects humans and other large mammals (e.g., cows and sheep). C. meleagridis infects avians (e.g., turkeys and chickens) and humans. Feces from infected animals, including humans, can contaminate water supplies and recreational water with viable oocysts despite standard chlorination (90). Person-to-person transmission, primarily among men who engage in oral-anal sex, also has been observed. Young children with cryptosporidial diarrhea also might infect adults, especially during diapering. Scrupulous handwashing, use of barriers during anal sex, and other hygiene measures might help prevent person-to-person transmission. Clinical Manifestations The most common presentation of cryptosporidiosis is the acute or subacute onset of profuse, nonbloody watery diarrhea, frequently accompanied by nausea, vomiting, and lower abdominal cramping (151). Fever is present in approximately one third of patients. Malabsorption is often present. The epithelium of both the biliary tract and the pancreatic duct can be infected with Cryptosporidium. Cholangitis and pancreatitis occur among patients with prolonged disease (152). Diagnosis Cryptosporidium species cannot be cultivated in vitro. Diagnosis of cryptosporidiosis is primarily based on microscopic identification of the oocysts in stool or tissue. Oocysts stain red with varying intensities with a modified acid-fast technique; this technique allows for differentiation of the Cryptosporidium oocysts from yeasts that are similar in size and shape but are not acid fast. Oocysts also can be detected by direct immunofluorescent or enzyme-linked immunosorbent assays (153). No consensus exists on the optimal oocyst detection method in fecal samples. The modified acid-fast stain and a fluorescein labeled monoclonal antibody technique indicate comparability for diarrheal samples, but the immunofluorescent method is probably preferable for formed stool specimens. Cryptosporidium species and genotype identification requires molecular methods (e.g., PCR followed by sequencing). Cryptosporidial enteritis can be diagnosed on small intestinal biopsy sections by identification of developmental stages of Cryptosporidium organisms, found individually or in clusters, on the brush border of the mucosal epithelial surfaces. Organisms project into the lumen because of their intracellar but extracytoplasmic characteristics and appear basophilic with hematoxylin and eosin staining. Electron microscopy allows resolution of cellular detail. Among persons with profuse diarrheal illness, a single stool specimen is usually adequate for diagnosis. Among persons with less severe disease, repeat stool sampling is recommended, although no controlled studies have demonstrated the utility of three consecutive stool samples as is the case in Giardia duodenalis infection. Treatment Recommendations ART with immune restoration (an increase of CD4+ T lymphocyte count to >100 cells/µL) is associated with complete resolution of cryptosporidiosis (154,155), and all patients with cryptosporidiosis should be offered ART as part of the initial management of their infection (AII). No consistently effective pharmacologic or immunologic therapy directed specifically against C. parvum exists. Approximately 95 interventional agents have been tried for the treatment of cryptosporidiosis with no consistent success. Paromomycin, a nonabsorbable aminoglycoside that is indicated for the treatment of intestinal amebiasis, is effective in high doses for the treatment of cryptosporidiosis in animal models (156). A meta-analysis of 11 published paromomycin studies in humans reported a response rate of 67%. However, relapse was common in certain studies, with long-term success rates of only 33%. Two randomized controlled trials have compared paromomycin with placebo among patients with AIDS and cryptosporidiosis; modest, but statistically significant improvement in symptoms and oocyst shedding was demonstrated in one, but no difference from placebo was observed in the other (157,158). A small open-label study suggested a substantial benefit of paromomycin when used in combination with azithromycin, but few cures were noted (159). Therefore, efficacy data do not support a recommendation for the use of paromomycin for therapy, although the drug appears to be safe (CIII). Nitazoxanide, an orally administered nitrothiazole benzamide, has in vivo activity against a broad range of helminths, bacteria, and protozoa, including cryptosporidia (160-162). A short-term study among patients with HIV-1 infection documented increased cure rates compared with controls (based on clearance of organisms from stool and reduced rates of diarrhea) among patients with CD4+ T lymphocyte counts >50 cells/µL, but not in those with CD4+ T lymphocyte counts <50 cells/µL (161). Available data do not warrant a definite recommendation for use of this agent in this setting, but the drug has been approved by the U.S. Food and Drug Administration (FDA) for use in children and is expected to be approved for use in adults (CIII). Treatment of persons with cryptosporidiosis should include symptomatic treatment of diarrhea (AIII). Rehydration and repletion of electrolyte losses by either the oral or intravenous route is important. Severe diarrhea, which might be >10 L/day among patients with AIDS, often requires intensive support. Aggressive efforts at oral rehydration should be made with oral rehydration solutions that contain glucose, sodium bicarbonate, potassium, magnesium, and phosphorus (AIII). Treatment with antimotility agents can play an important adjunctive role in therapy, but these agents are not consistently effective (BIII). Loperamide or tincture of opium will often palliate symptoms. Octreotide, a synthetic octapeptide analog of naturally occurring somatostatin that is approved for the treatment of secreting tumor induced diarrhea, is no more effective than other oral antidiarrheal agents, and is generally not recommended (162) (DII). Monitoring and Adverse Events Patients should be closely monitored for signs and symptoms of volume depletion, electrolyte and weight loss, and malnutrition and should receive supportive treatment. Total parenteral nutrition might be indicated in certain patients (CIII). Management of Treatment Failure Supportive treatment and optimizing ART to achieve full virologic suppression are the only feasible approaches to the management of treatment failure (CIII). Prevention of Recurrence No drug regimens are proven to be effective in preventing the recurrence of cryptosporidiosis. Special Considerations During Pregnancy As with nonpregnant woman, initial treatment efforts should rely on rehydration and initiation of ART. Pregnancy should not preclude the use of ART.
MicrosporidiosisEpidemiologyMicrosporidia organisms are protists related to fungi, defined by the presence of a unique invasive organelle consisting of a single polar tube that coils around the interior of the spore (163,164). They are ubiquitous organisms and are likely zoonotic and/or waterborne in origin (165). The microsporidia reported as pathogens in humans include Encephalitozoon cuniculi, Encephalitozoon hellem, Encephalitozoon (Septata) intestinalis, Enterocytozoon bieneusi, Trachipleistophora hominis, Trachipleistophora anthropopthera, Pleistophora species, P. ronneeafyi, Vittaforma (Nosema) corneae, Microsporidium sp., Nosema ocularum, Brachiola (Nosema) connori, Brachiola vesiculatum, and Brachiola (Nosema) algerae (163-169). In the pre-ART era, reported prevalence rates of microsporidiosis varied between 2% and 70% among HIV-1-infected patients with diarrhea, depending on the diagnostic techniques employed and the patient population described (163-166). The incidence of microsporidiosis has declined dramatically with the widespread use of effective ART. In the immunosuppressed host, microsporidiosis is most commonly observed when the CD4+ T lymphocyte count is <100 cells/µL (163-166). Clinical Manifestations The most common manifestation of microsporidiosis is gastrointestinal tract infection with diarrhea; however, encephalitis, ocular infection, sinusitis, myositis, and disseminated infection are also described (163-166). Clinical syndromes might vary by infecting species. Enterocytozoon bieneusi is associated with malabsorption, diarrhea, and cholangitis. Encephalitozoon cuniculi is associated with hepatitis, encephalitis, and disseminated disease. Encephalitozoon (Septata) intestinalis is associated with diarrhea, disseminated infection, and superficial keratoconjuctivitis. Encephalitozoon hellem is associated with superficial keratoconjunctivitis, sinusitis, respiratory disease, prostatic abscesses, and disseminated infection. Nosema, Vittaforma, and Microsporidium are associated with stromal keratitis following trauma in immunocompetent hosts. Pleistophora, Brachiola, and Trachipleistophora are associated with myositis. Trachipleistophora is associated with encephalitis and disseminated disease. Diagnosis Although microsporidia belonging to the genera Encephalitozoon, Brachiola (B. algerae), Vittaforma (V. corneae), and Trachipleistophora have been cultivated in vitro, E. bieneusi has not been successfully cultivated in vitro. Effective morphologic demonstration of microsporidia by light microscopy can be accomplished by staining methods that produce differential contrast between the spores of the microsporidia and the cells and debris in clinical samples (e.g., stool). In addition, because of the small size of the spores (1-5 mm), adequate magnification (e.g., 1,000X) is required for visualization. Chromotrope 2R, calcofluor white (fluorescent brightener), and Uvitex 2B (fluorescent brightener) are useful as selective stains for microsporidia in stool and other body fluids (167-169). In biopsy specimens, microsporidia can be visualized with Giemsa, Brown-Hopps Gram stain, acid-fast staining, Warthin-Starry silver staining, hematoxylin and eosin, or Chromotrope 2A (169). In gastrointestinal disease, examination of three stools with chromotrope and chemofluorescent stains is often sufficient for diagnosis. If stool examination is negative and microsporidiosis is suspected, a small bowel biopsy should be performed. If the etiologic agent is encephalitozoonidae or Trachipleistophora, examination of urine often reveals the organism. Determination of the species of microsporidia causing disease can be made by the morphology of the organism demonstrated by transmission electron microscopy or by PCR using species or genus specific primers (169). Treatment Recommendations ART with immune restoration (an increase of CD4+ T lymphocyte count to >100 cells/µL) is associated with resolution of symptoms of enteric microsporidiosis, including that caused by E. bieneusi (170-172). All patients should be offered ART as part of the initial management of their infection (AII). Nevertheless, data indicate that microsporidia are suppressed but not eliminated (171). No specific therapeutic agent is active against E. bieneusi infection. A controlled clinical trial suggests that E. bieneusi might respond to oral fumagillin (60 mg/day), a water insoluble antibiotic made by Aspergillus fumigatus (173,174) (BII). However, fumagillin is not available for systemic use in the United States (173,174). One report indicates that 60 days of nitazoxanide might resolve chronic diarrhea caused by E. bieneusi in the absence of ART (175). However, the effect might be minimal among patients with low CD4+ T cell counts. Nitazoxanide is approved for use among children and is expected to be approved by the FDA for use among adults. Albendazole and fumagillin have demonstrated consistent activity against other microsporidia in vitro and in vivo (176-181). Albendazole, a benzimidazole that binds to b-tubulin, has activity against many species of microsporidia, but it is not effective for Enterocytozoon infections, although fumagillin has activity in vitro and in vivo. Albendazole is recommended for initial therapy of intestinal and disseminated (not ocular) microsporidiosis caused by microsporidia other than E. bieneusi (178,181) (AII). Itraconazole also might be useful in disseminated disease when combined with albendazole especially in infections caused by Trachipleistophora or Brachiola (CIII). Ocular infections caused by microsporidia should be treated with topical Fumidil B (fumagillin bicylohexylammonium) in saline (to achieve a concentration of 70 mg/mL of fumagillin) (180) (BII). Topical fumagillin is the only formulation available for treatment in the United States and is investigational. Although clearance of microsporidia from the eye can be demonstrated, the organism often is still present systemically and can be detected in the urine or in nasal smears. In such cases, the use of albendazole as a companion systemic agent is recommended (BIII). Metronidazole and atovaquone are not active in vitro or in animal models and should not be used to treat microsporidiosis (DII). Fluid support should be offered if diarrhea has resulted in dehydration (AIII). Malnutrition and wasting should be treated with nutritional supplementation (AIII). Monitoring and Adverse Events Albendazole side effects are rare but hypersensitivity (rash, pruritis, fever), neutropenia (reversible), CNS effects (dizziness, headache), gastrointestinal disturbances (abdominal pain, diarrhea, nausea, vomiting), hair loss (reversible), and elevated hepatic enzymes (reversible) have been reported. Albendazole is not carcinogenic or mutagenic. Topical fumagillin has not been associated with substantial side effects. Oral fumagillin has been associated with thrombocytopenia, which is reversible on stopping the drug. Management of Treatment Failure Supportive treatment and optimizing ART to attempt to achieve full virologic suppression are the only feasible approaches to the management of treatment failure (CIII). Prevention of Recurrence Treatment for ocular microsporidiosis should be continued indefinitely because recurrence or relapse might follow treatment discontinuation (BIII). Whether treatment can be safely discontinued after immune restoration with ART is unknown, although it is reasonable, on the basis of the experience with discontinuation of secondary prophylaxis (chronic maintenance therapy) for other opportunistic infections during advanced HIV-1 disease, to discontinue chronic maintenance therapy if patients remain asymptomatic with regard to signs and symptoms of microsporidiosis and have a sustained (e.g. >6 months) increase in their CD4+ T lymphocyte counts to levels >200 cells/µL after ART (CIII). Special Considerations During Pregnancy Among animals (i.e., rats and rabbits), albendazole is embryotoxic and teratogenic at dosages of 30 mg/kg body weight. Therefore, albendazole is not recommended for use among pregnant women (DIII). However, well-controlled studies in human pregnancy have not been performed. Systemic fumagillin has been associated with increased resorption and growth retardation in rats. No data on use in human pregnancy are available. However, because of the antiangiogenic effect of fumagillin, this drug should not be used among pregnant women (EIII). Topical fumagillin has not been associated with embryotoxic or teratogenic effects among pregnant women and might be considered when therapy with this agent is appropriate (CIII).
Mycobacterium tuberculosis DiseaseEpidemiologyIn the United States, overall case rates of TB disease are declining with approximately 15,000 new cases reported in 2002 (182). HIV testing is recommended for suspected or confirmed cases of TB, but this is not uniformly practiced. Therefore, the percentage of TB patients with HIV-1 infection in the United States can only be estimated. In 1999, approximately 10% of all TB cases in the United States were known to be HIV-1 infected. The World Health Organization (WHO) estimates that TB is the cause of death for 11% of all AIDS patients (183). The percentage and absolute number of patients with TB disease who are HIV-1 infected is declining in the United States because of improved infection-control practices and better diagnosis and treatment of both HIV-1 infection and TB. With increased voluntary counseling and testing and the increasing use of treatment for latent TB infection, TB disease will probably continue to decrease among HIV-1-infected persons in the United States and Western Europe (184). Persons at high risk for TB in the United States include injection-drug users, persons from high prevalence countries, and those who live or work in congregate settings. TB disease occurs among HIV-1-infected persons at all CD4+ T lymphocyte counts. The clinical manifestations might be altered depending on the degree of immunosuppression. Those with more advanced immunosuppression (CD4+ T lymphocyte count <200 cells/µL) are more likely to have extrapulmonary or disseminated disease. In areas where TB is endemic, certain patients have higher CD4+ T lymphocyte counts at the time HIV-1-related TB disease develops; in countries with low rates of TB disease (e.g., United States and countries in Western Europe), more patients have advanced HIV-1 disease at the time TB develops. TB disease in persons with HIV-1 infection can develop immediately after exposure (i.e., primary disease) or as a result of progression after establishment of latent TB infection (i.e., reactivation disease). Primary TB has been reported in certain group outbreaks, particularly in persons with advanced immune suppression, and might account for one third or more of cases of TB disease in the HIV-infected population (185). Progression to disease among those with latent TB infection is more likely among HIV-1-infected than in HIV-uninfected persons (186). HIV-uninfected persons with a positive tuberculin skin test (TST) result have a 5%-10% lifetime risk for developing TB, compared with a 7%-10% annual risk in the HIV-1-infected person with a positive TST result. Patients with TB disease have higher HIV-1 viral loads and a more rapid progression of their HIV-1 illness than comparable HIV-1-infected patients without TB (187). Clinical Manifestations The clinical, radiographic, and histopathologic presentation of HIV-1-related TB disease is heavily influenced by the degree of immunodeficiency (188,189). With CD4+ T lymphocyte counts >350 cells/µL, HIV-1-related TB appears like TB among HIV-uninfected persons. The majority of patients have disease limited to the lungs, and common chest radiographic manifestations include upper lobe fibronodular infiltrates with or without cavitation (190). However, extrapulmonary disease is more common in HIV-1-infected persons than in non-HIV-infected persons. When extrapulmonary disease occurs in HIV-1-infected persons, clinical manifestations are not substantially different from those described in HIV-uninfected patients. With increasing degrees of immunodeficiency, extrapulmonary TB, with or without pulmonary involvement, becomes more common. At CD4+ T lymphocyte counts <50 cells/µL, extrapulmonary TB (pleuritis, pericarditis, and meningitis) is common. Among severely immunocompromised patients, TB can be a severe systemic disease with high fevers, rapid progression, and sepsis syndrome. The chest radiographic findings of TB disease in advanced AIDS are markedly different compared with those among patients with less severe HIV-1 infection; lower lobe, middle lobe, and miliary infiltrates are common and cavitation is less common. Patients with HIV-1 infection and pulmonary TB can have sputum smears and culture results positive for acid-fast bacilli (AFB) or M. tuberculosis, respectively, even with a normal chest radiograph. Histopathological findings are also affected by the degree of immunodeficiency. Patients with relatively intact immune function have typical granulomatous inflammation associated with TB disease. With progressive immunodeficiency, granulomas become poorly formed or can be completely absent (189). Diagnosis Suspicion of TB, and assiduous efforts to obtain appropriate diagnostic specimens are important in diagnosing HIV-1-related TB disease. The evaluation of suspected HIV-1-related TB should always include a chest radiograph. Sputum samples for AFB smear and culture should be obtained from patients with pulmonary symptoms, cervical adenopathy, or chest radiographic abnormalities. Sputum samples from a substantial fraction of cases of pulmonary TB are negative by direct smear microscopy. Nucleic-acid amplification (NAA) tests are useful in providing rapid identification of M. tuberculosis from sputum smear-positive specimens, but false-negative results can occur among patients with TB disease. The positive predictive value of NAA tests are decreased in persons who have sputum smear-negative results. Among patients with signs of extrapulmonary TB, needle aspiration of skin lesions, nodes, pleural, or pericardial fluid might allow for rapid diagnosis, culture, and susceptibility testing. Tissue biopsy is helpful among patients with negative fine-needle aspirates. Among patients with signs of disseminated disease, mycobacterial blood culture might allow a definitive diagnosis. Mycobacterial blood culture is more sensitive for diagnosis of TB among severely immunodeficient patients. Among patients with relatively intact immune function, the yield of sputum smear and culture examinations is similar to that of HIV-uninfected adults, with positive smear results being more common among patients with cavitary pulmonary involvement (191). TST is positive in the majority of patients with pulmonary disease and CD4+ T lymphocyte counts >200 cells/µL. Among patients with more severe immunodeficiency, sputum smear and culture examinations become somewhat less sensitive, and TST has limited diagnostic value because it is often negative (192). However, the yield of mycobacterial stain and culture of specimens from extrapulmonary sites (node aspirates and pleural and pericardial fluid) is higher among patients with advanced immunodeficiency compared with HIV-uninfected adults (193-195). Smear-positive specimens from these sites probably represent a high burden of organisms resulting from lack of effective immune response to mycobacteria and inability to limit mycobacterial replication and kill the organisms. A positive smear result in any of these specimens (sputum, needle aspirate, tissue biopsy) represents some form of mycobacterial disease but does not always represent TB. However, because TB is the most virulent mycobacterial pathogen and can be spread from person to person if pulmonary involvement is present, patients with smear-positive results should be treated for TB disease until definitive mycobacterial species identification is made. Drug susceptibility testing and adjustment of the treatment regimen based on the results are critical to the successful treatment of TB and to prevention of transmission of drug-resistant M. tuberculosis in the community. Therefore, for all patients with TB disease, testing for susceptibility to first line agents (isoniazid [INH], rifampin [RIF], and ethambutol [EMB]) should be performed, regardless of the source of the specimen. Pyrazinamide (PZA) susceptibility testing should be performed on an initial isolate if there is a sufficiently high prevalence of PZA resistance in the community. Second-line drug susceptibility testing should be performed only in reference laboratories and should be limited to specimens from patients who have had previous therapy, who are contacts of patients with drug-resistant TB disease, who have demonstrated resistance to rifampin or to other first-line drugs, or who have positive cultures after >3 months of treatment (185). Treatment Recommendations Treatment of HIV-1-related TB disease should follow the general principles developed for TB treatment among non-HIV-infected persons (AI). Early diagnosis and treatment are critical. Because of the severity of TB disease among immunocompromised patients, directly observed therapy (DOT) is strongly recommended for patients with HIV-1-related TB (AI). Multiple drugs and DOT are used to provide effective therapy, to prevent acquired drug resistance during treatment, and to allow cure with a relatively short course of treatment (6-9 months). HIV-1-infected patients have other social and medical needs and treatment success is enhanced by a case-management approach, which incorporates assistance with all of these needs (enhanced DOT) in addition to providing DOT. Multiple concerns should be considered in the treatment of HIV-1-associated TB disease. First, treatment is effective, but the optimal duration of treatment is uncertain. Second, acquired drug resistance is unusual with the use of DOT, but does occur among HIV-1-infected persons. Third, the risk for acquired rifamycin resistance has led to specific recommendations about dosing frequency. Finally, the use of potent ART among patients being treated for TB is complicated by overlapping drug toxicity profiles, drug-drug interactions, and an increase in TB manifestations during immune reconstitution (paradoxical reactions). Recent studies indicate that, with careful attention to these complicating factors, the prognosis of HIV-1-associated TB disease can be substantially improved with the provision of potent ART (AII), although the optimal relative timing between anti-TB and HIV therapy is uncertain. Treatment of drug susceptible TB disease in HIV-1-infected adults should include the use of a 6-month regimen consisting of an initial phase of INH, RIF or rifabutin, PZA, and EMB given for 2 months followed by INH and RIF (or rifabutin) for 4 months when the disease is caused by organisms known or presumed to be susceptible to first-line anti-TB drugs (185) (AI). When the organism is susceptible to INH, RIF, and PZA, EMB should be discontinued (AI). The optimal duration of therapy for HIV-1-related TB disease remains controversial. Studies in developing countries have shown that patients with HIV-1-related TB respond well to standard 6-month treatment regimens, with rates of treatment failure and relapse similar to those of HIV-uninfected patients (196). However, it is unclear whether these results are applicable to patients with advanced HIV-1 disease and TB. While awaiting definitive randomized comparisons in HIV-1-infected patients with TB disease, 6 months of therapy is probably adequate for the majority of cases, but prolonged therapy (up to 9 months) is recommended (as in HIV-negative patients) for patients with a delayed clinical or bacteriological response to therapy (symptomatic or positive culture results at or after 2 months of therapy, respectively) or perhaps with cavitary disease on chest radiograph (BII). Intermittent dosing (twice- or thrice- weekly) facilitates DOT by decreasing the total number of encounters required between the patient and the provider, making observed therapy more practical to deliver. However, once- or twice-weekly dosing has been associated with an increased rate of acquired rifamycin resistance among patients with advanced HIV-1 disease (CD4+ T lymphocyte count <100 cells/µL). Acquired rifamycin resistance was relatively common with once-weekly rifapentine plus INH and also occurred in trials of twice-weekly rifabutin plus INH and twice-weekly RIF plus INH (197-199). Therefore, once-weekly rifapentine is contraindicated among HIV-1-infected patients (EI), and it is recommended that RIF- and rifabutin-based regimens be given at least three times a week for patients with TB and advanced HIV-1 disease (CD4+ T lymphocyte count <100 cells/µL) (AII). Although treatment approaches to this population need to be further evaluated in prospective trials, a prudent management strategy consists of daily DOT during the first 2 months of therapy and thrice-weekly DOT during the continuation phase of anti-TB therapy (198) (BII). Monitoring and Adverse Events Close follow-up, consisting of clinical, bacteriologic, and occasionally, laboratory and radiographic evaluations, is essential to ensure treatment success. In patients with pulmonary TB, at least one sputum specimen for microscopic examination and culture should be obtained at monthly intervals until two consecutive specimens are negative on culture (AII). Drug susceptibility tests should be repeated on isolates from patients who have positive cultures after 3 months of treatment. Patients who have positive cultures after 4 months of treatment should be considered as having failed therapy and managed accordingly. For patients with extrapulmonary TB, the frequency and types of evaluations will depend on the sites involved and the ease with which specimens can be obtained. A detailed clinical assessment should be performed at least monthly to identify possible medication intolerance and to assess adherence. As a routine, monitoring blood tests for patients being treated with first-line drugs unless baseline abnormalities were identified is unnecessary (AII). More frequent clinical and laboratory monitoring is indicated for patients with underlying liver disease, including hepatitis C co-infection. INH, RIF, and PZA all can cause drug-induced hepatitis, and the risk might be increased in patients taking other potentially hepatotoxic agents or in persons with underlying liver dysfunction. However, because of the effectiveness of these drugs (particularly INH and RIF), they should be used, if at all possible, even in the presence of preexisting liver disease (AIII). Frequent clinical and laboratory monitoring should be performed to detect any exacerbation. Independent of HIV status for all patients with TB disease, multiple treatment options exist if serum aminotransaminases are >3 times the upper limit of normal before the initiation of treatment, and the abnormalities are not thought to be caused by TB disease. One option is to use standard therapy with frequent monitoring. A second option is to treat with RIF, EMB, and PZA for 6 months, avoiding INH (BII). A third option is to treat with INH and RIF for 9 months, supplemented by EMB for the first 2 months, thereby avoiding PZA (BII). Among patients with severe liver disease, a regimen with only one hepatotoxic agent, generally RIF plus EMB, can be given for 12 months, preferably with another agent, such as a fluoroquinolone, for the first 2 months (CIII). As previously indicated, treatment might need to be lengthened for patients who are HIV-1-infected. For patients who develop worsening hepatic function on treatment, a specialist should be consulted. Tests to monitor hepatotoxicity (aminotransferases, bilirubin, and alkaline phosphatase), renal function (serum creatinine), and platelet count should be obtained for all patients started on treatment for TB. At each monthly visit, patients taking EMB should be asked about possible visual disturbances including blurred vision or scotomata. Monthly testing of visual acuity and color discrimination is recommended for patients taking doses that, on a milligram per kilogram basis, are greater than those listed in recommended doses and for patients receiving the drug for >2 months. Patients with TB disease caused by strains of M. tuberculosis resistant to at least INH and RIF (multidrug-resistant [MDR]) are at high risk for treatment failure and further acquired drug resistance. Such patients should be referred to or have consultation obtained from specialized treatment centers as identified by the local or state health departments or CDC. Although patients with strains resistant to RIF alone have a better prognosis than patients with MDR strains, they are also at increased risk for treatment failure and additional resistance and should be managed in consultation with an expert. Antiretroviral Therapy in the Management of TB Disease and Paradoxical Reactions Rifamycin drugs are essential components of short-course regimens for treatment of TB disease. However, substantial adverse pharmacologic interactions occur between rifamycins and commonly used antiretroviral drugs (e.g., PIs and NNRTIs) as a result of changes in drug metabolism resulting from induction of the hepatic cytochrome P-450 (CYP450) enzyme system (200,201). Of the available rifamycins, RIF is the most potent CYP450 inducer and rifabutin has substantially less inducing activity. Despite such interactions, a rifamycin should generally not be excluded from the TB treatment regimen among patients receiving potent ART, except in unusual circumstances (AII). Either RIF or rifabutin can be used with NRTIs (199,200). Rifabutin can be used with certain PIs or NNRTIs (other than delavirdine) and has fewer problematic drug interactions than does rifampin (Table 5). Adjustments in rifabutin or elements of the ART regimen might be necessary with certain combinations. Two antiretroviral drug regimens have been associated with a favorable outcome when administered with RIF: efavirenz (potentially using an increased dose of 800 mg/day) plus 2 NRTIs and ritonavir (600 mg twice daily) plus 2 NRTIs. Serum concentrations of nevirapine might be adequate even in the presence of concentrations of RIF associated with enzyme induction, but clinical data are lacking. RIF should not be used with nelfinavir, saquinavir, indinavir, amprenavir, atazanavir, or dual PI combinations using low dose ritonavir (<200 mg twice daily) for which dosing guidelines are not available (EII). The optimal time for initiating ART during TB treatment is unknown. Because of the risk for prolonged airborne transmission of M. tuberculosis, initiation of treatment for TB disease should never be delayed (AI). Early initiation of ART (within the first 2-4 weeks after the start of TB therapy) might decrease HIV-1 disease progression but might be associated with a relatively high incidence of side effects and paradoxical reactions (some severe enough to warrant discontinuation of both antiretroviral and anti-TB drugs). Delaying the initiation of ART for 4-8 weeks after starting antituberculous therapy has the potential advantages of being better able to ascribe a specific cause for a drug side effect, decreasing the severity of paradoxical reactions, and decreasing the adherence challenge for the patient. Until controlled studies are conducted to evaluate the optimal time for starting ART in patients with HIV-1-associated TB disease, this decision should be individualized on the basis of the patient's initial response to TB therapy, occurrence of side effects, and acceptance of multidrug ART. For these considerations, health-care providers should avoid beginning the simultaneous administration of both potent ART and combination chemotherapy for TB; most health-care providers would wait at least 4-8 weeks (BIII). Patients already receiving ART at the time treatment for TB is started require a careful assessment of the ART regimen and, if necessary, changes to ensure optimum treatment of the HIV-1 infection in the setting of TB therapy. Because of the difficulties associated with the accurate diagnosis of an adverse drug reaction and in determining the responsible agent, the first-line anti-TB drugs should not be stopped permanently without strong evidence that the anti-TB drug was the cause of the reaction. In such situations, consultation with an expert in treating TB in persons with HIV-1 infection is recommended. Patients might experience temporary exacerbation of symptoms, signs, or radiographic manifestations of TB disease after beginning anti-TB treatment. This phenomenon is termed a paradoxical (or immune reconstitution) reaction. This reaction occurs among non-HIV-1-infected persons, but it is more common among those with HIV-1 infection, particularly those treated with ART. These reactions presumably develop as a consequence of reconstitution of immune responsiveness brought about by ART or perhaps by treatment of TB itself (202-206). Signs of a paradoxical reaction can include high fevers, increase in size and inflammation of involved lymph nodes, new lymphadenopathy, expanding central nervous system lesions, worsening of pulmonary parenchymal infiltrations, and increasing pleural effusions. Such findings should be attributed to a paradoxical reaction only after a thorough evaluation has excluded other possible causes, especially TB therapy failure. A paradoxical reaction that is not severe should be treated symptomatically with nonsteroidal anti-inflammatory agents without a change in anti-TB or antiretroviral therapy (BIII). Approaches to the management of severe reactions (e.g., high fever, airway compromise from enlarging lymph nodes, enlarging serosal fluid collections, and sepsis syndrome) have not been studied. However, case reports have documented improvements with the use of prednisone or methylprednisolone used at a dose of approximately 1mg/kg body weight and gradually reduced after 1-2 weeks (202-206) (CIII). Management of Drug Resistance and Treatment Failure If resistance to INH (with or without resistance to streptomycin) is detected, INH and streptomycin, if used, should be discontinued and the patient treated with a 6-month regimen of RIF, PZA, and EMB, which is nearly as effective as the conventional INH-containing regimen (BII). Alternatively, treatment with RIF and EMB for 12 months can be used, preferably with PZA during at least the initial 2 months (BII). Treatment regimens for TB disease caused by RIF monoresistant strains are less effective, and patients infected with these strains are at increased risk for relapse and treatment failure. A minimum of 12-18 months of treatment with INH, EMB, and a fluoroquinolone (e.g., levofloxacin) with PZA administered during the first 2 months is recommended (BIII). An injectable agent (e.g., amikacin or capreomycin) might be included in the first 2-3 months for patients with severe disease. Patients with MDR-TB are at high risk for treatment failure and relapse and require especially close follow-up during (and often after) treatment. Treatment regimens for MDR-TB should be individualized, taking into account the resistance pattern, relative activities of available anti-TB agents, the extent of disease, and presence of co-morbid conditions. The management of MDR-TB is complex and should be undertaken only by an experienced specialist or in close consultation with specialized treatment centers (AIII). Prevention of Recurrence Secondary prophylaxis (chronic maintenance therapy) for patients who have successfully completed a recommended regimen of treatment for TB disease is unnecessary (DII). However, reinfection can occur. Special Considerations During Pregnancy HIV-1-infected pregnant women who do not have documentation of a negative TST result during the preceding year should be tested during pregnancy. The frequency of anergy is not increased during pregnancy, and routine anergy testing for HIV-1-infected pregnant women is not recommended (207-210). The diagnostic evaluation for TB disease in pregnant women is the same as for nonpregnant adults. Chest radiographs with abdominal shielding result in minimal fetal radiation exposure. An increase in pregnancy complications, including preterm birth, low birthweight, and intrauterine growth retardation, might be observed among pregnant women with either pulmonary or extrapulmonary TB not confined to the lymph nodes, especially when treatment is not begun until late in pregnancy (207-213). Therapy of TB disease during pregnancy should be the same as for the nonpregnant adult, but with attention given to the following considerations (BIII):
Experience during pregnancy with the majority of the second line drugs for TB is limited. MDR-TB in pregnancy should be managed in consultation with an expert. Therapy should not be withheld because of pregnancy (AIII). The following concerns should be considered when selecting second-line anti-TB drugs for use among pregnant women:
Disseminated Mycobacterium avium Complex DiseaseEpidemiologyOrganisms of the Mycobacterium avium complex (MAC) are ubiquitous in the environment (219-224). M. avium is the etiologic agent in >95% of patients with AIDS who develop disseminated MAC disease (219-224). An estimated 7%-12% of adults have been previously infected with MAC, although rates of disease vary in different geographic locations (220,221,224). Although certain epidemiologic associations have been identified, no environmental exposure or behavior has been consistently associated with the subsequent development of MAC disease in susceptible persons. The mode of transmission for MAC infection is thought to be through inhalation, ingestion, or inoculation through respiratory or gastrointestinal tract portals of entry. Household or close contacts of those with MAC disease do not appear to be at increased risk for experiencing disease, and person-to-person transmission is unlikely. In the absence of effective combination ART or chemoprophylaxis in those with advanced immunosuppression, the incidence of disseminated MAC disease among persons with AIDS ranges from 20%-40% (220-222). For those with a CD4+ T lymphocyte count <100 cells/µL who are receiving effective prophylaxis or those who have responded to ART with a sustained increase in CD4+ T lymphocyte count to levels >100-200 cells/µL, the overall incidence rate has been estimated at 2 cases per 100 person-years. Most cases of MAC disease occur among persons with CD4+ T lymphocyte counts <50 cells/µL. Other factors that are associated with increased susceptibility to MAC disease are high plasma HIV-1 RNA levels (>100,000 copies/mL), previous opportunistic infections (particularly CMV disease), previous colonization of the respiratory or gastrointestinal tract with MAC, and reduced in vitro lymphoproliferative immune responses to M. avium antigens, possibly reflecting defects in T-cell repertoire. Clinical Manifestations MAC disease among patients with AIDS, in the absence of ART, is generally a disseminated multiorgan infection (225-229). Early symptoms might be minimal and might precede detectable intermittent or continuous mycobacteremia by several weeks. Symptoms include fever, night sweats, weight loss, fatigue, diarrhea, and abdominal pain. Immune reconstitution inflammatory syndrome, characterized by focal lymphadenitis with fever, is a systemic inflammatory response with signs and symptoms that are clinically indistinguishable from active infection and is similar to paradoxical reactions observed with TB disease (230-232). Bacteremia is absent. The syndrome has been described among patients with subclinical or established MAC disease and advanced immunosuppression who begin ART and have a rapid and marked increase in CD4+ T lymphocyte count (>100 cells/µL). This syndrome might be benign and self-limited or might be severe and require systemic anti-inflammatory therapy to alleviate clinical symptoms. Other localized manifestations of MAC disease have been reported most commonly among persons who are receiving and who have responded to ART. Localized syndromes include cervical or mesenteric lymphadenitis, pneumonitis, pericarditis, osteomyelitis, skin or soft tissue abscesses, genital ulcers, or CNS infection. Laboratory abnormalities particularly associated with disseminated MAC disease include anemia (often out of proportion to that expected for stage of HIV-1 disease) and elevated liver alkaline phosphatase (219-225,233-235). Hepatomegaly, splenomegaly, or lymphadenopathy (paratracheal, retroperitoneal, para-aortic, or less commonly peripheral) might be identified on physical examination or by radiographic or other imaging studies. Other focal physical findings or laboratory abnormalities might occur in the context of those localized disease syndromes previously described. Diagnosis A confirmed diagnosis of disseminated MAC disease is based on compatible clinical signs and symptoms coupled with the isolation of MAC from cultures of blood, bone marrow, or other normally sterile tissue or body fluids (233-239). Use of an Isolator® (Wampole Laboratories, Cranbury, New Jersey) or a similar blood culture system and inoculation of blood into Bactec 12B liquid medium, or direct inoculation of specimens into Bactec 13A bottles (Bactec; Becton Dickinson, Sparks, Maryland), followed by radiometric detection of growth, are recommended (237). Species identification should be performed using specific DNA probes, high performance liquid chromatography, or biochemical tests. Other ancillary studies provide supportive diagnostic information, including AFB smear and culture of stool or biopsy material obtained from tissues or organs, radiographic imaging of the abdomen or mediastinum for detection of lymphadenopathy, or other studies aimed at isolation of organisms from focal infection sites. Treatment Recommendations Initial treatment of MAC disease should consist of two antimycobacterial drugs to prevent or delay the emergence of resistance (240-255) (AI). Clarithromycin is the preferred first agent (250) (AI); it has been studied more extensively than azithromycin and appears to be associated with more rapid clearance of MAC from the blood (240,250,254,255). However, azithromycin can be substituted for clarithromycin when drug interactions or clarithromycin intolerance preclude the use of clarithromcyin (AII). Ethambutol is the recommended second drug (250) (AI). Some clinicians would add rifabutin as a third drug (CI). One randomized clinical trial demonstrated that the addition of rifabutin to the combination of clarithromycin and ethambutol for the treatment of disseminated MAC disease improved survival, and in two randomized clinical trials, this approach reduced emergence of drug resistance (246,251). These studies were completed before the availability of effective ART. The addition of rifabutin should be considered in persons with advanced immunosuppression (CD4+ T lymphocyte count <50 cells/µL), high mycobacterial loads (>2 log10 colony forming units/mL of blood), or in the absence of effective ART, settings in which mortality is increased and emergence of drug resistance are most likely (CIII). If rifabutin cannot be used because of drug interactions or intolerance (Table 5), a third or fourth drug may be selected from among either the fluoroquinolones (ciprofloxacin or levofloxacin) or parenteral amikacin (Table 6), although data supporting a survival or microbiologic benefit when these agents are added have not been compelling (240-253) (CIII). Patients who have had disseminated MAC disease diagnosed and who have not previously been treated with or are not receiving potent ART should generally have ART initiated simultaneously or within 1-2 weeks of initiation of antimycobacterial therapy for MAC disease (CIII). If ART has already been instituted, it should be continued and optimized for patients with disseminated MAC disease, unless drug interactions preclude the safe concomitant use of antiretroviral and antimycobacterial drugs (CIII). Persons who have symptoms of moderate-to-severe intensity because of an immune recovery inflammatory syndrome in the setting of ART should receive treatment initially with nonsteroidal, anti-inflammatory agents (CIII). If symptoms fail to improve, short-term (4-8 weeks) systemic corticosteroid therapy, in doses equivalent to 20-40 mg of oral prednisone QD, has been successful (256,257) (CIII). Monitoring and Adverse Events Improvement in fever and a decline in quantity of mycobacteria in blood or tissue can be expected within 2-4 weeks after initiation of appropriate therapy. However, for those with more extensive disease or advanced immunosuppression, clinical response might be delayed. A repeat blood culture for MAC should be obtained 4-8 weeks after initiation of antimycobacterial therapy for patients who fail to have a clinical response to their initial treatment regimen (i.e., little or no reduction in fever or systemic symptoms). Adverse effects with clarithromycin and azithromycin include nausea, vomiting, abdominal pain, abnormal taste, and elevations of liver transaminase levels or hypersensitivity reactions. Doses of clarithromycin >1 g per day for treatment of disseminated MAC disease have been associated with increased mortality and should not be used (258) (EI). Rifabutin doses of >450 mg/day have been associated with higher risk for adverse drug interactions when used with clarithromycin or other drugs that inhibit cytochrome p450 isoenzyme 3A4 and might be associated with a higher risk for experiencing uveitis or other adverse drug reactions (259,260). Management of Treatment Failure Treatment failure is defined by the absence of a clinical response and the persistence of mycobacteremia after 4-8 weeks of treatment. Testing of MAC isolates for susceptibility to clarithromycin and azithromycin is recommended for patients who fail to microbiologically respond to initial therapy, relapse after an initial response, or develop MAC disease while receiving clarithromycin or azithromycin for prophylaxis; testing for susceptibility to clarithromycin, azithromycin, ethambutol, and rifabutin might be helpful in this setting, although the predictive value for ethambutol and rifabutin with regard to response to therapy has not been established. The majority of patients who failed clarithromycin or azithromycin primary prophylaxis in clinical trials had isolates susceptible to these drugs at the time MAC disease was detected (237,240,241,251,261). Bactec® radiometric broth macrodilution is the recommended method for testing M. avium for susceptibility to antimicrobial agents (237,250,261). Minimum inhibitory concentrations (MICs) of >32 µg/mL for clarithromycin or >256 µg/mL for azithromycin are the suggested thresholds for determination of resistance based on the Bactec® method for radiometric susceptibility testing (237,251,261). Because the number of drugs with demonstrated clinical activity against MAC is limited, results of susceptibility testing should be used to construct a new multidrug regimen consisting of at least two new drugs not previously used and to which the isolate is susceptible from among the following: ethambutol, rifabutin, ciprofloxacin or levofloxacin, or amikacin (CIII). Whether continuing clarithromycin or azithromycin in the face of resistance provides additional benefit is unknown (CIII). Clofazimine should not be used on the basis of the lack of efficacy demonstrated in randomized trials and the association with increased mortality (247,249) (EII). Other second-line agents (e.g., ethionamide, thiacetazone [not available in the United States], or cycloserine) have been anecdotally combined with these drugs as salvage regimens. However, their role in this setting is not well defined. Among patients who have failed initial treatment for MAC disease or who have antimycobacterial drug resistant MAC disease, optimizing ART is an important adjunct to second-line or salvage therapy for MAC disease (AIII). Adjunctive treatment of MAC disease with immunomodulators has not been thoroughly studied, and data are insufficient to support a recommendation for use (DIII). Interferon-gamma, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, and interleukin-12, either alone or in combination with other cytokines, appear to inhibit intracellular replication or enhance in vitro intracellular killing of M. avium (256,257,262,263). Use of these immunomodulators would be a logical adjuvant treatment for those who fail conventional antimycobacterial therapy. Prevention of Recurrence Adult and adolescent patients with disseminated MAC disease should receive lifelong secondary prophylaxis (chronic maintenance therapy) (AII), unless immune reconstitution occurs as a result of ART (250,264-268). Patients are at low risk for recurrence of MAC when they have completed a course of >12 months of treatment for MAC, remain asymptomatic with respect to MAC signs and symptoms, and have a sustained increase (e.g., >6 months) in their CD4+ T lymphocyte counts to >100 cells/µL after ART. Although the numbers of patients who have been evaluated remain limited and recurrences could occur, on the basis of these observations and on inference from more extensive data indicating the safety of discontinuing secondary prophylaxis for other opportunistic infections during advanced HIV-1 disease, discontinuing chronic maintenance therapy among such patients is reasonable (250,253,267,268) (BII). Certain health-care providers recommend obtaining a blood culture for MAC, even for asymptomatic patients, before discontinuing therapy to substantiate that disease is no longer active, but it is not clear how often a positive culture will be obtained in such patients. Secondary prophylaxis should be reintroduced if the CD4+ T lymphocyte count decreases to <100 cells/µL (AIII). Special Considerations During Pregnancy Diagnostic considerations and indications for treatment are the same as among nonpregnant adults. Azithromycin is preferred over clarithromycin as the second agent with ethambutol or rifabutin because of the occurrence of birth defects in mice and rats associated with clarithromycin (269-272) (BIII). Limited data among humans do not indicate an increased risk for defects among 122 women taking clarithromycin during the first trimester, although an increased rate of spontaneous abortions was noted (271). Limited data are available on the use of azithromycin during the first trimester in humans (271,272).
Bacterial Respiratory DiseaseEpidemiologyBacterial pneumonia is a common cause of HIV-1 related morbidity (273,274). Incidence of approximately 100 cases per 1,000 HIV-1-infected persons per year have been reported, a rate much higher than in the noninfected population (273). In a study comparing rates among cohorts with similar other risk factors for bacterial pneumonia, those with HIV-1 infection were 7.8 times more likely to develop bacterial pneumonia than HIV-seronegative persons (274). For certain persons, bacterial pneumonia is a symptom of HIV-1 disease. Patients can develop serious pneumococcal infections with relatively preserved CD4+ T lymphocyte counts. |
