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1999 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus FREE

USPHS/IDSA Prevention of Opportunistic Infections Working Group
[+] Article and Author Information

*Only filters capable of removing particles 1 µm in diameter should be considered. Filters that provide the greatest assurance of oocyst removal include those that operate by reverse osmosis, those labeled as absolute 1-µm filters, and those labeled as meeting NSF (National Sanitation Foundation) standard no. 53 for cyst removal. The nominal 1-µm filter rating is not standardized, and many filters in this category might not be capable of removing 99% of oocysts.

†Sources of bottled water (e.g., wells, springs, municipal tap-water supplies, rivers, and lakes) and methods for its disinfection differ; therefore, all brands should not be presumed to be free of cryptosporidial oocysts. Water from wells and springs is much less likely to be contaminated by oocysts than water from rivers or lakes. Treatment of bottled water by distillation or reverse osmosis ensures oocyst removal. Water passed through an absolute 1-µm filter or a filter labeled as meeting NSF standard no. 53 for cyst removal before bottling will provide nearly the same level of protection. Use of nominal 1-µm filters by bottlers as the only barrier to Cryptosporidia might not result in the removal of 99% of oocysts.

‡ Letters and Roman numerals in parentheses indicate the strength of the recommendation and the quality of evidence supporting it (Table 1).


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1999;131(11):873-908. doi:10.7326/0003-4819-131-11-199912070-00022
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In August 1999, agencies of the U.S. Public Health Service (USPHS), in collaboration with the Infectious Diseases Society of American (IDSA), published 1999 Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus (HIV) (1). These guidelines are an update of those prepared in 1995 and 1997 and published in several venues, including Annals of Internal Medicine (2, 3). They are intended primarily for health care providers who care for HIV-infected persons and are reproduced here in an effort to reach and as a service to all internists who care for HIV-infected patients.

Single copies of the 1999 USPHS/IDSA guidelines can be obtained from the AIDS Treatment Information Service (ATIS) by calling 800-448-0440, 301-217-0023 (international), or 800-243-7012 (TYY) or by downloading the document from the ATIS Web site at http://www.hivatis.org.

1. USPHS/IDSA Prevention of Opportunistic Infections Working Group. 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep. 1999; 48(RR-10):1-66.

2. USPHS/IDSA Prevention of Opportunistic Infections Working Group. USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: a summary. Ann Intern Med. 1996; 124:348-68.

3. USPHS/IDSA Prevention of Opportunistic Infections Working Group. 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. Ann Intern Med. 1997; 127:922-46.

The working group was chaired by Henry Masur, MD, National Institutes of Health, Bethesda, MD; Jonathan E. Kaplan, MD, Centers for Disease Control and Prevention, Atlanta; and King K. Holmes, MD, PhD, University of Washington, Seattle.

Members of the group included Beverly L. Alston, MD (National Institutes of Health, Bethesda, MD); Neil Ampel, MD (University of Arizona, Tucson); Jean R. Anderson, MD (Johns Hopkins University, Baltimore); A. Cornelius Baker (National Association of People with AIDS, Washington, DC); David Barr (Forum for Collaborative HIV Research, Washington, DC); John G. Bartlett, MD (Johns Hopkins University, Baltimore); John E. Bennett, MD (National Institutes of Health, Bethesda, MD); Constance A. Benson, MD (University of Colorado, Denver); Samual A. Bozzette, MD (University of California, San Diego); Richard E. Chaisson, MD (Johns Hopkins University, Baltimore); Clyde S. Crumpacker, MD (Harvard Medical Center, Boston); Judith S. Currier, MD, MSc (University of California-Los Angeles Medical Center, Los Angeles); Lawrence Deyton, MD, MSPH (U.S. Department of Veterans Affairs, Washington, DC); W. Lawrence Drew, MD, PhD (Mt. Zion Medical Center, University of California-San Francisco, San Francisco); William R. Duncan, PhD (National Institutes of Health, Bethesda, MD); Robert W. Eisinger, PhD (National Institutes of Health, Bethesda, MD); Wafaa El-Sadr, MD, MPH, MPA (Harlem Hospital, New York); Judith Feinberg, MD (Holmes Hospital, Cincinnati); Kenneth A. Freedberg, MD, MSc (Boston University School of Medicine, Boston); Hansjakob Furrer, MD (University Hospital, Berne, Switzerland); John W. Gnann Jr., MD (University of Alabama, Birmingham); Mark J. Goldberger, MD, MPH (U.S. Food and Drug Administration, Rockville, MD); Sue Goldie, MD, PhD (Harvard School of Public Health, Boston); Eric P. Goosby, MD (U.S. Department of Health and Human Services, Washington, DC); Peter A. Gross, MD (Hackensack Medical Center, Hackensack, NJ); Richard Hafner, MD (National Institutes of Health, Bethesda, MD); Diane Havlir, MD (University of California, San Diego); Thomas M. Hooton, MD (Harborview Medical Center, Seattle); Douglas A. Jabs, MD (Johns Hopkins University, Baltimore); Mark A. Jacobson, MD (University of California, San Francisco); Edward Janoff, MD (Veterans Administration Medical Center, Minneapolis); Mari Kitahata, MD, PhD (University of Washington, Seattle); Joseph V. Kovacs, MD (National Institutes of Health, Bethesda, MD); Catherine Leport, MD (Hospital Bichat-Claude Bernard, Paris); Myron J. Levin, MD (University of Colorado Health Science Center, Denver); Juan C. Lopez, MD (Hospital Universatario Gregorio Maranon, Madrid); Michael Marco (Treatment Action Group, New York); Douglas L. Mayers, MD (Henry Ford Hospital, Detroit); David A. Melnick, MD (Kaiser Permanente, Springfield, VA); Lynne M. Mofenson, MD (National Institutes of Health, Bethesda, MD); Julio S.G. Montaner, MD (St. Paul's Hospital, Vancouver); Richard Moore, MD (Johns Hopkins University, Baltimore); James Neaton, PhD (University of Minnesota, Minneapolis); Charles Nelson (National Association of People with AIDS, Washington, DC); Joseph F. O'Neill, MD, MS, MPH (Health Resources and Services Administration, Rockville, MD); Joel Palefsky, MD (University of California, San Francisco); Alice Pau, PharmD (National Institutes of Health, Bethesda, MD); John P. Phair, MD (Northwestern University, Chicago); Stephen Piscitelli, PharmD (National Institutes of Health, Bethesda, MD); Michael A. Polis, MD, MPH (National Institutes of Health, Bethesda, MD); Thomas C. Quinn, MD (Johns Hopkins Hospital, Baltimore); Peter Reiss, MD, PhD (University of Amsterdam, Amsterdam); David Rimland, MD (Veterans Administration Medical Center, Atlanta); Cynthia L. Sears, MD (Johns Hopkins University, Baltimore); Leonard Seeff, MD (National Institutes of Health, Bethesda, MD); Kent A. Sepkowitz, MD (Memorial Sloan-Kettering Cancer Center, New York); Thomas G. Slama, MD (National Foundation for Infectious Diseases, Indianapolis); Elaine M. Sloand, MD (National Institutes of Health, Bethesda, MD); Stephen A. Spector, MD (University of California, La Jolla); David L. Thomas, MD, MPH (Johns Hopkins University, Baltimore); Russell B. Van Dyke, MD (Tulane School of Medicine, New Orleans, LA); D. Heather Watts, MD (National Institutes of Health, Bethesda, MD); L. Joseph Wheat, MD (Indiana University School of Medicine, Indianapolis); Scott M. Whitcup, MD (National Institutes of Health, Bethesda, MD); Paige Williams, PhD (Harvard School of Public Health, Boston); Thomas C. Wright Jr., MD (Columbia University College of Physicians and Surgeons, New York).

Participants from the Centers for Disease Control and Prevention, Atlanta, included Kenneth G. Castro, MD, Kevin M. DeCock, MD, DTM&H, Scott F. Dowell, MD, MPH, Mark S. Dworkin, MD, MPHTM, Clare Dykewicz, MD, MPH, Tedd Ellerbrock, MD, Rana Hajjeh, MD, Scott Holmberg, MD, MPH, David R. Holtgrave, PhD, Harold W. Jaffe, MD, Jeffrey L. Jones, MD, Dennis D. Juranek, DVM, MSc, Eric Mast, MD, MPH, Thomas Navin, MD, Phil E. Pellett, PhD, William C. Reeves, MD, MPH, John A. Stewart, MD, and M. Elsa Villarino, MD, MPH.

This report was prepared by Jonathan E. Kaplan, MD (Division of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases and Division of HIV/AIDS Prevention—Surveillance and Epidemiology, National Center for HIV, STD, and TB Prevention) in collaboration with Henry Masur, MD (National Institutes of Health) and King K. Holmes, MD, PhD (University of Washington).

In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) in persons infected with human immunodeficiency virus (HIV) (13). These guidelines, written for health-care providers and patients, were revised in 1997 and published in MMWR (4), Clinical Infectious Diseases (5), Annals of Internal Medicine (6), American Family Physician (7), and Pediatrics (8); an accompanying editorial appeared in JAMA (9). Response to these guidelines (e.g., the many requests for reprints and observations from health-care providers) suggests they have served as a valuable reference for HIV care providers. Because the 1995 and 1997 guidelines included ratings indicating the strength of each recommendation and the quality of supporting evidence, readers were able to assess the relative importance of each recommendation.

Since AIDS was first recognized nearly 20 years ago, remarkable progress has been made in improving the quality and duration of life of HIV-infected persons. During the first decade of the epidemic, this improvement occurred because of better recognition of opportunistic disease processes, better therapy for acute and chronic complications, and the introduction of chemoprophylaxis against Pneumocystis carinii pneumonia (PCP), toxoplasmosis, Mycobacterium avium complex (MAC) disease, and bacterial infections. Trimethoprim-sulfamethoxazole (TMP-SMZ) was shown to reduce the incidence not only of PCP but also of toxoplasmosis and bacterial infections.

The second decade of the epidemic has witnessed extraordinary progress in developing highly active antiretroviral therapies (HAARTs) as well as continuing progress in preventing and treating individual OIs. HAART has reduced the incidence of OIs and extended life substantially (10). HAART is the most effective approach to preventing OIs and should be considered for all HIV-infected persons who qualify for such therapy. However, some patients are not ready or able to take HAART, and others have tried HAART regimens, but therapy has failed. Such patients will benefit from prophylaxis against OIs. In addition, prophylaxis against specific OIs continues to provide survival benefits even among persons who are receiving HAART (11).

Because important new data concerning the prevention of opportunistic diseases have emerged since 1997, the USPHS and the IDSA reconvened the Prevention of Opportunistic Infections Working Group on March 4 and 5, 1999, to determine which recommendations warranted revision. Participants included representatives from federal agencies, universities, and professional societies, as well as community health-care providers and patient advocates. Much attention was focused on recent data related to the advisability of discontinuing OI prophylaxis (primary prophylaxis and prophylaxis against recurrence) among persons whose CD4+ T-lymphocyte counts have increased to above prophylaxis thresholds because of HAART. The OI Working Group also addressed two pathogens not previously considered—human herpesvirus type 8 (HHV-8) and hepatitis C virus (HCV). In addition, working group members reviewed data concerning the prevention of all common HIV-associated OIs. In revising these current guidelines, as in earlier editions of the guidelines, the group considered factors such as incidence of disease; severity of disease in terms of morbidity and mortality; level of immunosuppression at which disease is most likely to occur; feasibility, efficacy, and cost of preventive measures; impact of intervention on quality of life; and drug toxicities, drug interactions, and the potential for drug resistance to develop.

During the development of these revised guidelines, working group members reviewed published manuscripts as well as abstracts and material presented at professional meetings if complete manuscripts providing data were available for review. A review of the data that served as the basis for the revisions and additional information discussed at the meeting but not deemed sufficient to justify a revision of the recommendations will be published separately in Clinical Infectious Diseases.

Primary changes in the disease-specific recommendations that follow include

  • The addition of statements concerning discontinuation of prophylaxis against specific OIs when the CD4+ T-lymphocyte count increases in response to HAART.

  • New recommendations regarding HHV-8 and HCV.

  • New recommendations concerning injection drug users.

  • New recommendations about short-course chemoprophylaxis against tuberculosis in HIV-infected persons with positive tuberculin skin tests (TSTs).

  • Changes in secondary prophylaxis (chronic maintenance therapy) recommended to prevent the recurrence of MAC and cytomegalovirus (CMV) disease.

  • Caution against using fluconazole during pregnancy.

  • Statements concerning the use of varicella and rotavirus vaccines among HIV-infected infants.

These guidelines developed by the OI Working Group were made available for public comment through announcements in the Federal Register and MMWR. The final document is endorsed by the USPHS and IDSA as well as by the Infectious Diseases Society of Obstetrics and Gynecology and the National Foundation for Infectious Diseases.

For each of the 19 diseases covered in this report, specific recommendations are provided that address a] prevention of exposure to the opportunistic pathogen, b) prevention of the first episode of disease, and c) prevention of disease recurrence. Recommendations are rated by a revised version of the IDSA rating system (Table 1) (12). In this system, the letters A through E signify the strength of the recommendation for or against a preventive modality, and Roman numerals I through III indicate the quality of evidence supporting the recommendation.

Table Jump PlaceholderTable 1.  System Used To Rate the Strength of Recommendations and Quality of Supporting Evidence

Because of their length and complexity, the rest of the tables and figure in this report are grouped together, following the references. The tables and figure appear in the following order: dosages for prophylaxis to prevent first episode of opportunistic disease in HIV-infected adults and adolescents (Table 2); dosages for prophylaxis to prevent recurrence of opportunistic disease in HIV-infected adults and adolescents (Table 3); effects of food on drugs used to treat OIs (Table 4); effects of medications on drugs used to treat OIs (Table 5); effects of OI medications on drugs commonly administered to HIV-infected persons (Table 6); adverse effects of drugs used to manage HIV infection (Table 7); dosages of drugs for prevention of OIs for persons with renal insufficiency (Table 8); costs of agents recommended for the prevention of OIs in adults with HIV infection (Table 9); immunologic categories for HIV-infected children (Table 10); immunization schedule for HIV-infected children (Figure); dosages for prophylaxis to prevent first episode of opportunistic disease in HIV-infected infants and children (Table 11); dosages for prophylaxis to prevent recurrence of opportunistic disease in HIV-infected infants and children (Table 12); and criteria for discontinuing and restarting OI prophylaxis for adult patients with HIV infection (Table 13). Recommendations advising patients how to prevent exposure to opportunistic pathogens appear in the Appendix at the end of the text.

Table Jump PlaceholderTable 2.  Prophylaxis To Prevent First Episode of Opportunistic Disease in Adults and Adolescents Infected with Human Immunodeficiency Virus
Table Jump PlaceholderTable 3.  Prophylaxis To Prevent Recurrence of Opportunistic Disease (after Chemotherapy for Acute Disease) in Adults and Adolescents Infected with Human Immunodeficiency Virus
Table Jump PlaceholderTable 4.  Effects of Food on Drugs Used To Prevent Opportunistic Infections
Table Jump PlaceholderTable 5.  Effects of Medications on Drugs Used To Prevent Opportunistic Infections
Table Jump PlaceholderTable 6.  Effects of Opportunistic Infection Medications on Drugs Commonly Administered to Persons Infected with Human Immunodeficiency Virus
Table Jump PlaceholderTable 7.  Adverse Effects of Opportunistic Infection Medications Used in the Management of Human Immunodeficiency Virus Infection
Table Jump PlaceholderTable 8.  Dosages of Drugs for Primary Prevention or Maintenance Therapy for Persons with Opportunistic Infections and Renal Insufficiency
Table Jump PlaceholderTable 9.  Wholesale Acquisition Costs of Agents Recommended for the Prevention of Opportunistic Infections in Adults Infected with Human Immunodeficiency Virus
Table Jump PlaceholderTable 10.  Immunologic Categories for Human Immunodeficiency Virus-Infected Children Based on Age-Specific CD4+ T-Lymphocyte Counts and Percentage of Total Lymphocytes
Grahic Jump Location
Figure.
Recommended immunization schedule for human immunodeficiency virus-infected children.
Grahic Jump Location
Table Jump PlaceholderTable 11.  Prophylaxis To Prevent First Episode of Opportunistic Disease in Infants and Children Infected with Human Immunodeficiency Virus
Table Jump PlaceholderTable 12.  Prophylaxis To Prevent Recurrence of Opportunistic Disease (after Chemotherapy for Acute Disease) in HIV-Infected Infants and Children
Table Jump PlaceholderTable 13.  Criteria for Discontinuing and Restarting Opportunistic Infection Prophylaxis for Adults with HIV Infection

This report is oriented toward the prevention of specific OIs in HIV-infected persons in the United States and other industrialized countries. Recommendations for use of antiretroviral therapy, which is designed to prevent immunologic deterioration and delay the need for many of the chemoprophylactic strategies described in this report, are published elsewhere (10), as are integrated approaches to the care of HIV-infected persons (13).

Single copies of this report can be obtained from the AIDS Treatment Information Service (ATIS) by calling 800-448-0440, 301-217-0023 (international), or 800-243-7012 (TTY), and the report can be downloaded from the ATIS website at http://www.hivatis.org. In addition, pamphlets for patients are available from ATIS and also can be accessed on the Centers for Disease Control and Prevention's Division of HIV/AIDS Prevention homepage at http://www.cdc.gov/hiv.

New data on prevention of OIs in HIV-infected persons are emerging, and randomized controlled trials addressing some unresolved issues in OI prophylaxis are ongoing. The OI Working Group has therefore developed a mechanism for routinely and periodically reviewing emerging data and for updating these guidelines on a regular basis. The most recent information will be available from the ATIS website at http://www.hivatis.org.

Pneumocystis carinii Pneumonia
Prevention of Exposure

(1) Although some authorities recommend that persons with HIV infection who are at risk for PCP not share a hospital room with a patient who has PCP, data are insufficient to support this recommendation as standard practice (CIII).

Prevention of Disease
Initiation of Primary Prophylaxis

(2) Adults and adolescents who have HIV infection (including pregnant women and those on HAART) should receive chemoprophylaxis against PCP if they have a CD4+ T-lymphocyte count of <200/µL (AI) or a history of oropharyngeal candidiasis (AII) (14). Persons who have a CD4+ T-lymphocyte percentage of <14% or history of an AIDS-defining illness but do not otherwise qualify should be considered for prophylaxis (BII) (1516). When monitoring the CD4+ T-lymphocyte count at least every 3 months is not possible, initiation of chemoprophylaxis at a CD4+ T-lymphocyte count of >200 but <250 cells/µL also should be considered (BII) (15).

(3) TMP-SMZ is the recommended prophylactic agent (AI) (1618). One double-strength tablet per day is the preferred regimen (AI) (17). However, one single-strength tablet per day (19) is also effective and might be better tolerated (AI). One double-strength tablet three times per week is also effective (BI) (20). TMP-SMZ at a dose of one double-strength tablet per day confers cross-protection against toxoplasmosis (21) and some common respiratory bacterial infections (17, 22). Lower doses of TMP-SMZ also might confer such protection. For patients who have an adverse reaction that is not life-threatening, treatment with TMP-SMZ should be continued if clinically feasible; for those who have discontinued such therapy because of an adverse reaction, reinstitution of TMP-SMZ should be strongly considered after the adverse event has resolved (AII). Patients who have experienced adverse events, especially fever and rash, might better tolerate reintroduction of the drug with a gradual increase in dose (desensitization) as per published regimens (BI) (2324) or reintroduction of TMP-SMZ at a reduced dose or frequency (CIII); up to 70% of patients can tolerate such reinstitution of therapy (22).

(4) If TMP-SMZ cannot be tolerated, prophylactic regimens that can be recommended as alternatives include dapsone (BI) (17), dapsone plus pyrimethamine plus leucovorin (BI) (2526), aerosolized pentamidine administered by the Respirgard IITM nebulizer (Marquest, Englewood, Colorado) (BI) (18), and atovaquone (BI) (2728). Atovaquone appears to be as effective as aerosolized pentamidine (28) or dapsone (BI) (27) but is substantially more expensive than the other regimens. For patients seropositive for Toxoplasma gondii who cannot tolerate TMP-SMZ, recommended alternatives to TMP-SMZ for prophylaxis against both PCP and toxoplasmosis include dapsone plus pyrimethamine (BI) (2526) or atovaquone with or without pyrimethamine (CIII). The following regimens generally cannot be recommended as alternatives because data regarding their efficacy for PCP prophylaxis are insufficient for a firm recommendation: aerosolized pentamidine administered by other nebulization devices, intermittently administered parenteral pentamidine, oral pyrimethamine plus sulfadoxine, oral clindamycin plus primaquine, and intravenous trimetrexate. However, clinicians may consider using these agents in unusual situations in which the recommended agents cannot be administered (CIII).

Discontinuation of Primary Prophylaxis

(5) Initial reports from three prospective observational studies (2931), one retrospective review (32), and one randomized trial (33) suggest that PCP prophylaxis can be safely discontinued in patients responding to HAART with a sustained increase in CD4+ T-lymphocyte counts from <200 cells/µL to >200 cells/µL. Such reports have mostly included patients receiving primary prophylaxis (no prior episode of PCP) and protease inhibitor-containing regimens. In these studies, median follow-up ranged from 6 to 12 months and the median CD4+ T-lymphocyte count at the time prophylaxis was discontinued was >300 cells/µL. At the time PCP prophylaxis was discontinued, many patients had sustained suppression of HIV plasma RNA levels below detection limits of the available assays. Although optimal criteria for discontinuing PCP prophylaxis are still being assessed, providers may wish to discontinue prophylaxis when patients have sustained a CD4+ T-lymphocyte count of >200 cells/µL for at least 3-6 months (CII). Additional criteria might include sustained reduction in viral load for at least 3-6 months (CIII).

Restarting Primary Prophylaxis

(6) No data are available to guide recommendations for reinstituting primary prophylaxis. Pending the availability of such data, a reasonable approach would be to use the criteria for initiating prophylaxis described on page 876 (CIII).

Prevention of Recurrence

(7) Adults and adolescents who have a history of PCP should be administered chemoprophylaxis (i.e., secondary prophylaxis or chronic maintenance therapy) with the regimens described on page 876 in order to prevent recurrence (AI) (16).

Discontinuation of Secondary Prophylaxis (Chronic Maintenance Therapy)

(8) Although patients receiving secondary prophylaxis (prior episode of PCP) might also be at low risk for PCP when their CD4+ T-lymphocyte counts increase to >200 cells/µL, inadequate numbers of patients have been evaluated to warrant a recommendation to discontinue prophylaxis in such patients.

Special Considerations
Children

(9) Children born to HIV-infected mothers should be administered prophylaxis with TMP-SMZ beginning at 4-6 weeks of age (34) (AII). Prophylaxis should be discontinued for children who are subsequently found not to be infected with HIV. HIV-infected children and children whose infection status remains unknown should continue to receive prophylaxis for the first year of life. The need for subsequent prophylaxis should be determined on the basis of age-specific CD4+ T-lymphocyte count thresholds (Table 11) (AII). The safety of discontinuing prophylaxis in HIV-infected children receiving HAART has not been studied.

(10) Children who have a history of PCP should be administered lifelong chemoprophylaxis to prevent recurrence (AI) (34).

Pregnant Women

(11) Chemoprophylaxis for PCP should be administered to pregnant women as is done for other adults and adolescents (AIII). TMP-SMZ is the recommended prophylactic agent; dapsone is an alternative. Because of theoretical concerns regarding possible teratogenicity associated with drug exposures during the first trimester, providers may choose to withhold prophylaxis during the first trimester. In such cases, aerosolized pentamidine may be considered because of its lack of systemic absorption and the resultant lack of exposure of the developing embryo to the drug (CIII).

Prevention of Exposure

(1) HIV-infected persons should be tested for immunoglobulin G (IgG) antibody to Toxoplasma soon after the diagnosis of HIV infection to detect latent infection with T. gondii (BIII).

(2) All HIV-infected persons, but particularly those who lack IgG antibody to Toxoplasma, should be counseled about the various sources of toxoplasmic infection. They should be advised not to eat raw or undercooked meat, particularly undercooked pork, lamb, or venison (BIII). Specifically, meat should be cooked to an internal temperature of 150 °F (65.5 °C); meat cooked until it is no longer pink inside generally has an internal temperature of 165 °F (73.8 °C) and therefore satisfies this requirement. HIV-infected persons should wash their hands after contact with raw meat and after gardening or other contact with soil; in addition, they should wash fruits and vegetables well before eating them raw (BIII). If the patient owns a cat, the litter box should be changed daily, preferably by an HIV-negative, nonpregnant person; alternatively, the patient should wash the hands thoroughly after changing the litter box (BIII). Patients should be encouraged to keep their cats inside and not to adopt or handle stray cats (BIII). Cats should be fed only canned or dried commercial food or well-cooked table food, not raw or undercooked meats (BIII). Patients need not be advised to part with their cats or to have their cats tested for toxoplasmosis (EII).

Prevention of Disease
Initiation of Primary Prophylaxis

(3) Toxoplasma-seropositive patients who have a CD4+ T-lymphocyte count of <100/µL should be administered prophylaxis against toxoplasmic encephalitis (TE) (AII) (21). The double-strength tablet daily dose of TMP-SMZ recommended as the preferred regimen for PCP prophylaxis appears to be effective against TE as well and is therefore recommended (AII) (21). If patients cannot tolerate TMP-SMZ, the recommended alternative is dapsone-pyrimethamine, which is also effective against PCP (BI) (2526). Atovaquone with or without pyrimethamine also may be considered (CIII). Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, or clarithromycin cannot be recommended on the basis of current data (DII). Aerosolized pentamidine does not protect against TE and is not recommended (EI) (17, 21).

(4) Toxoplasma-seronegative persons who are not taking a PCP prophylactic regimen known to be active against TE should be retested for IgG antibody to Toxoplasma when their CD4+ T-lymphocyte count declines below 100/µL to determine whether they have seroconverted and are therefore at risk for TE (CIII). Patients who have seroconverted should be administered prophylaxis for TE as described above (AII).

Discontinuation of Primary Prophylaxis

(5) Limited data suggest that discontinuing prophylaxis for patients whose CD4+ T-lymphocyte counts increase to >100 cells/µL in response to HAART is associated with a low risk for TE. However, the numbers of patients who have been evaluated are insufficient to recommend routine discontinuation of prophylaxis in such patients. Persons whose CD4+ T-lymphocyte count remains <200 cells/µL or who have a history of PCP or oropharyngeal candidiasis still require prophylaxis against PCP, as noted previously.

Prevention of Recurrence

(6) Patients who have had TE should be administered lifelong suppressive therapy (secondary prophylaxis or chronic maintenance therapy) with drugs active against Toxoplasma to prevent relapse (AI) (3536). The combination of pyrimethamine plus sulfadiazine and leucovorin is highly effective for this purpose (AI) (3536). A commonly used regimen for patients who cannot tolerate sulfa drugs is pyrimethamine plus clindamycin (BI); however, only the combination of pyrimethamine plus sulfadiazine appears to provide protection against PCP as well (AII).

Discontinuation of Secondary Prophylaxis (Chronic Maintenance Therapy)

(7) The numbers of patients who have stopped maintenance therapy after responding to HAART are insufficient to warrant recommending discontinuation of maintenance therapy.

Special Considerations
Children

(8) TMP-SMZ, when administered for PCP prophylaxis, also provides prophylaxis against toxoplasmosis. Atovaquone might also provide protection (CIII). Children aged >12 months who qualify for PCP prophylaxis and who are receiving an agent other than TMP-SMZ or atovaquone should have serologic testing for Toxoplasma antibody (BIII), because alternative drugs for PCP prophylaxis might not be effective against Toxoplasma. Severely immunosuppressed children who are not receiving TMP-SMZ or atovaquone who are found to be seropositive for Toxoplasma should be administered prophylaxis for both PCP and toxoplasmosis (i.e., dapsone plus pyrimethamine) (BIII).

Pregnant Women

(9) TMP-SMZ can be administered for prophylaxis against TE as described for PCP (AIII). However, because of the low incidence of TE during pregnancy and the possible risk associated with pyrimethamine treatment, chemoprophylaxis with pyrimethamine-containing regimens can reasonably be deferred until after pregnancy (CIII). For prophylaxis against recurrent TE, the health-care provider and clinician should be well informed about the benefit of lifelong therapy and the concerns about teratogenicity of pyrimethamine. Most clinicians favor lifelong therapy for the mother, given the high likelihood that disease will recur promptly if therapy is stopped (AIII).

(10) In rare cases, HIV-infected pregnant women who have serologic evidence of remote toxoplasmic infection have transmitted Toxoplasma to the fetus in utero. Pregnant HIV-infected women who have evidence of primary toxoplasmic infection or active toxoplasmosis (including TE) should be evaluated and managed during pregnancy in consultation with appropriate specialists (BIII). Infants born to women who have serologic evidence of infections with HIV and Toxoplasma should be evaluated for congenital toxoplasmosis (BIII).

Prevention of Exposure

(1) HIV-infected persons should be educated and counseled about the many ways that Cryptosporidium can be transmitted (BIII). Modes of transmission include having direct contact with infected adults, diaper-aged children, and infected animals; drinking contaminated water; coming into contact with contaminated water during recreational activities; and eating contaminated food.

(2) HIV-infected persons should avoid contact with human and animal feces. They should be advised to wash their hands after contact with human feces (e.g., diaper changing), after handling pets, and after gardening or other contact with soil. HIV-infected persons should avoid sexual practices that might result in oral exposure to feces (e.g., oral-anal contact) (BIII).

(3) HIV-infected persons should be advised that newborn and very young pets might pose a small risk for transmitting cryptosporidial infection, but they should not be advised to destroy or give away healthy pets. Persons contemplating the acquisition of a new pet should avoid bringing any animal that has diarrhea into their households, should avoid purchasing a dog or cat aged <6 months, and should not adopt stray pets. HIV-infected persons who wish to assume the small risk for acquiring a puppy or kitten aged <6 months should request that their veterinarian examine the animal's stool for Cryptosporidium before they have contact with the animal (BIII).

(4) HIV-infected persons should avoid exposure to calves and lambs and to premises where these animals are raised (BII).

(5) HIV-infected persons should not drink water directly from lakes or rivers (AIII).

(6) Waterborne infection also might result from swallowing water during recreational activities. HIV-infected persons should be aware that many lakes, rivers, and salt-water beaches and some swimming pools, recreational water parks, and ornamental water fountains might be contaminated with human or animal waste that contains Cryptosporidium. They should avoid swimming in water that is likely to be contaminated and should avoid swallowing water while swimming or playing in recreational waters (BIII).

(7) Several outbreaks of cryptosporidiosis have been linked to municipal water supplies. During outbreaks or in other situations in which a community “boil-water” advisory is issued, boiling water for 1 minute will eliminate the risk for cryptosporidiosis (AI). Use of submicron personal-use water filters(1) (home/office types) and/or bottled water(2) also might reduce the risk (CIII). The magnitude of the risk for acquiring cryptosporidiosis from drinking water in a nonoutbreak setting is uncertain, and current data are inadequate to recommend that all HIV-infected persons boil water or avoid drinking tap water in nonoutbreak settings. However, HIV-infected persons who wish to take independent action to reduce the risk for waterborne cryptosporidiosis may choose to take precautions similar to those recommended during outbreaks. Such decisions should be made in conjunction with health-care providers. Persons who opt for a personal-use filter or bottled water should be aware of the complexities involved in selecting appropriate products, the lack of enforceable standards for the destruction or removal of oocysts, the cost of the products, and the logistic difficulty of using these products consistently.

(8) Patients who take precautions to avoid acquiring cryptosporidiosis from drinking water should be advised that ice made from contaminated tap water also can be a source of infection (BII). Such persons also should be aware that fountain beverages served in restaurants, bars, theaters, and other places also might pose a risk because these beverages, as well as the ice they contain, are made from tap water. Nationally distributed brands of bottled or canned carbonated soft drinks are safe to drink. Commercially packaged noncarbonated soft drinks and fruit juices that do not require refrigeration until after they are opened (i.e., those that can be stored unrefrigerated on grocery shelves) also are safe. Nationally distributed brands of frozen fruit juice concentrate are safe if they are reconstituted by the user with water from a safe source. Fruit juices that must be kept refrigerated from the time they are processed to the time of consumption might be either fresh (unpasteurized) or heat-treated (pasteurized); only those juices labeled as pasteurized should be considered free of risk from Cryptosporidium. Other pasteurized beverages and beers also are considered safe to drink (BII). No data are available concerning survival of Cryptosporidium oocysts in wine.

(9) HIV-infected persons should avoid eating raw oysters because cryptosporidial oocysts can survive in oysters for more than 2 months and have been found in oysters taken from some commercial oyster beds (BIII). Cryptosporidium-infected patients should not work as food handlers, especially if the food to be handled is intended to be eaten without cooking (BII). Because most foodborne outbreaks of cryptosporidiosis are believed to have been caused by infected food handlers, more specific recommendations to avoid exposure to contaminated food cannot be made.

(10) In a hospital, standard precautions (i.e., use of gloves and hand washing after removal of gloves) should be sufficient to prevent transmission of cryptosporidiosis from an infected patient to a susceptible HIV-infected person (BII). However, because of the potential for fomite transmission, some experts recommend that HIV-infected persons, especially those who are severely immunocompromised, should not share a room with a patient with cryptosporidiosis (CIII).

Prevention of Disease

(11) No agents have been proven to be effective as chemoprophylaxis against cryptosporidiosis. Rifabutin or clarithromycin, when taken for MAC prophylaxis, were associated with a reduced risk for cryptosporidiosis in one study (37), but data are insufficient to warrant a recommendation for using these drugs.

Prevention of Recurrence

(12) No drug regimens are known to be effective in preventing the recurrence of cryptosporidiosis.

Special Considerations
Children

(13) At present, no data indicate that formula-preparation practices for infants should be altered in an effort to prevent cryptosporidiosis (CIII). However, in the event of a “boil-water” advisory, similar precautions for the preparation of infant formula should be taken as for drinking water for adults (AII).

Prevention of Exposure

(1) Other than general attention to hand washing and other personal hygiene measures, no precautions to reduce exposure can be recommended at this time.

Prevention of Disease

(2) No chemoprophylactic regimens are known to be effective in preventing microsporidiosis.

Prevention of Recurrence

(3) No chemotherapeutic regimens are known to be effective in preventing the recurrence of microsporidiosis.

Prevention of Exposure

(1) HIV-infected persons should be advised that certain activities and occupations might increase the likelihood of exposure to tuberculosis (BIII). These include volunteer work or employment in health-care facilities, correctional institutions, and shelters for the homeless, as well as in other settings identified as high risk by local health authorities. Decisions about whether to continue with activities in these settings should be made in conjunction with the health-care provider and should be based on factors such as the patient's specific duties in the workplace, the prevalence of tuberculosis in the community, and the degree to which precautions are taken to prevent the transmission of tuberculosis in the workplace (BIII). Whether the patient continues with such activities might affect the frequency with which screening for tuberculosis needs to be conducted.

Prevention of Disease

(2) When HIV infection is first recognized, the patient should receive a TST by administration of intermediate-strength (5-TU) purified protein derivative (PPD) by the Mantoux method (AI). Routine evaluation for anergy is not recommended. However, there are selected situations in which anergy evaluation might assist in guiding individual decisions about preventive therapy (38).

(3) All HIV-infected persons who have a positive TST result (≥ 5 mm of induration) should undergo chest radiography and clinical evaluation to rule out active tuberculosis. HIV-infected persons who have symptoms suggestive of tuberculosis should promptly undergo chest radiography and clinical evaluation regardless of their TST status (AII).

(4) All HIV-infected persons, regardless of age, who have a positive TST result yet have no evidence of active tuberculosis and no history of treatment or prophylaxis for tuberculosis should be administered preventive chemotherapy. Options include isoniazid daily (AII) or twice weekly (BI) for 9 months or 2 months of therapy with either rifampin and pyrazinamide (AI) or rifabutin and pyrazinamide (BIII) (38). Because HIV-infected persons are at risk for peripheral neuropathy, those receiving isoniazid should also receive pyridoxine (BIII). A decision to use a regimen containing either rifampin or rifabutin should be made after careful consideration of potential drug interactions, especially those related to protease inhibitors and nonnucleoside reverse transcriptase inhibitors (see Special Considerations/Drug Interactions on this page). Directly observed therapy should be used with intermittent dosing regimens (AI) and when otherwise operationally feasible (BIII) (38).

(5) HIV-infected persons who are close contacts of persons who have infectious tuberculosis should be administered preventive therapy—regardless of their TST results, age, or prior courses of chemoprophylaxis—after the diagnosis of active tuberculosis has been excluded (AII) (38). In addition to household contacts, such persons might also include contacts in the same drug-treatment or health-care facility, coworkers, and other contacts if transmission of tuberculosis is demonstrated.

(6) For persons exposed to isoniazid- and/or rifampin-resistant tuberculosis, the decision to use chemoprophylactic antimycobacterial agents other than isoniazid alone, rifampin plus pyrazinamide, or rifabutin plus pyrazinamide should be based on the relative risk for exposure to resistant organisms and should be made in consultation with public health authorities (AII).

(7) TST-negative, HIV-infected persons from risk groups or geographic areas with a high prevalence of Mycobacterium tuberculosis infection might be at increased risk for primary or reactivation tuberculosis. However, the efficacy of preventive therapy in this group has not been demonstrated. Decisions concerning the use of chemoprophylaxis in these situations must be considered individually.

(8) Although the reliability of the TST might diminish as the CD4+ T-lymphocyte count declines, annual repeat testing should be considered for HIV-infected persons who are TST-negative on initial evaluation and who belong to populations in which there is a substantial risk for exposure to M. tuberculosis (BIII). Clinicians also may consider repeating TSTs for persons whose immune function has improved because of HAART (i.e., those whose CD4+ T-lymphocyte count has increased to >200 cells/µL) (CIII). In addition to confirming tuberculous infection, TST conversion in an HIV-infected person should alert health-care providers to the possibility of recent M. tuberculosis transmission and should prompt notification of public health officials for investigation to identify a possible source case.

(9) The administration of bacille Calmette-Guérin (BCG) vaccine to HIV-infected persons is contraindicated because of its potential to cause disseminated disease (EII).

Prevention of Recurrence

(10) Chronic suppressive therapy for a patient who has successfully completed a recommended regimen of treatment for tuberculosis is not necessary (DII).

Special Considerations
Drug Interactions

(11) Rifampin should not be administered with protease inhibitors or nonnucleoside reverse transcriptase inhibitors (EI) (38). Rifabutin is an acceptable alternative but should not be used with the protease inhibitor hard-gel saquinavir; caution is also advised if the drug is coadministered with soft-gel saquinavir, but data are lacking. Rifabutin can be administered at one half the usual daily dose (i.e., reduce from 300 mg to 150 mg per day) with indinavir, nelfinavir, or amprenavir or with one fourth the usual dose (i.e., 150 mg every other day or three times a week) with ritonavir. Similarly, rifabutin should not be used with the nonnucleoside reverse transcriptase inhibitor delavirdine. Pharmacokinetic data suggest that rifabutin at an increased dose can be administered with efavirenz; a dose of 450 mg per day has been suggested (38). Information is lacking regarding coadministration of rifabutin with nevirapine.

Children

(12) Infants born to HIV-infected mothers should have a TST (5-TU PPD) at or before the age of 9-12 months and should be retested at least once a year (AIII). HIV-infected children living in households with TST-positive persons should be evaluated for tuberculosis (AIII); children exposed to a person who has active tuberculosis should be administered preventive therapy after active tuberculosis has been excluded, regardless of their TST results (AII).

Pregnant Women

(13) Chemoprophylaxis for tuberculosis is recommended during pregnancy for HIV-infected patients who have either a positive TST or a history of exposure to active tuberculosis, after active tuberculosis has been excluded (AIII). A chest radiograph should be obtained before treatment and appropriate abdominal/pelvic lead apron shields should be used to minimize radiation exposure to the embryo/fetus. When an HIV-infected person has not been exposed to drug-resistant tuberculosis, isoniazid daily or twice weekly is the prophylactic regimen of choice. Because of concerns regarding possible teratogenicity associated with drug exposures during the first trimester, providers may choose to initiate prophylaxis after the first trimester. Preventive therapy with isoniazid should be accompanied by pyridoxine to reduce the risk for neurotoxicity. Experience with rifampin or rifabutin during pregnancy is more limited, but anecdotal experience with rifampin has not been associated with adverse pregnancy outcomes. Pyrazinamide should generally be avoided, particularly in the first trimester, because of lack of information concerning fetal effects.

Prevention of Exposure

(1) Organisms of MAC are common in environmental sources such as food and water. Current information does not support specific recommendations regarding avoidance of exposure.

Prevention of Disease
Initiation of Primary Prophylaxis

(2) Adults and adolescents who have HIV infection should receive chemoprophylaxis against disseminated MAC disease if they have a CD4+ T-lymphocyte count of <50 cells/µL (AI) (4). Clarithromycin (3940) or azithromycin (41) are the preferred prophylactic agents (AI). The combination of clarithromycin and rifabutin is no more effective than clarithromycin alone for chemoprophylaxis and is associated with a higher rate of adverse effects than either drug alone; this combination should not be used (EI) (39). The combination of azithromycin with rifabutin is more effective than azithromycin alone; however, the additional cost, increased occurrence of adverse effects, potential for drug interactions, and absence of a difference in survival when compared with azithromycin alone do not warrant a routine recommendation for this regimen (CI) (41). In addition to their preventive activity for MAC disease, clarithromycin and azithromycin each confer protection against respiratory bacterial infections (BII). If clarithromycin or azithromycin cannot be tolerated, rifabutin is an alternative prophylactic agent for MAC disease (BI) (39, 4142). Tolerance, cost, and drug interactions are among the issues that should be considered in decisions regarding the choice of prophylactic agents for MAC disease. Particular attention to interactions with antiretroviral protease inhibitors and nonnucleoside reverse transcriptase inhibitors is warranted (see Special Considerations/Drug Interactions, page 883). Before prophylaxis is initiated, disseminated MAC disease should be ruled out by clinical assessment, which might include obtaining a blood culture for MAC if warranted. Because treatment with rifabutin could result in the development of resistance to rifampin in persons who have active tuberculosis, active tuberculosis should also be excluded before rifabutin is used for prophylaxis.

(3) Although the detection of MAC organisms in the respiratory or gastrointestinal tract might predict the development of disseminated MAC infection, no data are available on the efficacy of prophylaxis with clarithromycin, azithromycin, rifabutin, or other drugs in patients with MAC organisms at these sites and a negative blood culture. Therefore, routine screening of respiratory or gastrointestinal specimens for MAC cannot be recommended (DIII).

Discontinuation of Primary Prophylaxis

(4) Information from observational studies suggested a low rate of disseminated infection with MAC among persons who responded to HAART with an increase in CD4+ T-lymphocyte count from <50 cells/µL to >100 cells/µL (32, 43). Although the optimal criteria for discontinuing MAC prophylaxis remain to be defined, a reasonable option would be to consider discontinuing prophylaxis in patients with a CD4+ T-lymphocyte count of >100 cells/µL for a sustained period (e.g., >3-6 months) and sustained suppression of HIV plasma RNA for a similar period (CII).

Restarting Primary Prophylaxis

(5) No data are available on which to base recommendations for reinstituting prophylaxis. Pending the availability of such data, a reasonable approach would be to use the criteria for initiating prophylaxis described on this page (CIII).

Prevention of Recurrence

(6) Patients who have been treated for disseminated MAC disease should continue to receive full therapeutic doses of antimycobacterial agents for life (i.e., secondary prophylaxis or chronic maintenance therapy) (AII) (42). Unless good clinical or laboratory evidence of macrolide resistance exists, the use of a macrolide (clarithromycin or, alternatively, azithromycin) is recommended in combination with ethambutol (AII) with or without rifabutin (CI) (4445). Treatment of MAC disease with clarithromycin in a dose of 1000 mg twice a day is associated with a higher mortality rate than has been observed with clarithromycin administered at 500 mg twice a day; thus, the higher dose should not be used (EI) (4647). Clofazimine has been associated with an adverse clinical outcome in the treatment of MAC disease and should not be used (DII) (4748).

Discontinuation of Secondary Prophylaxis (Chronic Maintenance Therapy)

(7) Although patients receiving chronic maintenance therapy for MAC might be at low risk for recurrence of MAC when their CD4+ T-lymphocyte counts increase to >100 cells/µL following 6-12 months of HAART, the numbers of patients who have been evaluated are insufficient to warrant a recommendation to discontinue maintenance therapy in such patients.

Special Considerations
Drug Interactions

(8) Rifabutin should not be administered with certain protease inhibitors or nonnucleoside reverse transcriptase inhibitors (see Special Considerations/Drug Interactions in Tuberculosis section, page 881). Although protease inhibitors might also increase clarithromycin levels, no recommendation to adjust the dose of either clarithromycin or protease inhibitors can be made on the basis of existing data.

Children

(9) HIV-infected children aged <13 years who have advanced immunosuppression also can develop disseminated MAC infections, and prophylaxis should be offered to high-risk children according to the following CD4+ T-lymphocyte thresholds: children aged ≥ 6 years, <50 cells/µL; children aged 2-6 years, <75 cells/µL; children aged 1-2 years, <500 cells/µL; and children aged <12 months, <750 cells/µL (AII). For the same reasons that clarithromycin and azithromycin are the preferred prophylactic agents for adults, they should also be considered for children (AII); oral suspensions of both agents are commercially available in the United States. No liquid formulation of rifabutin suitable for pediatric use is commercially available in the United States. The safety of discontinuing MAC prophylaxis in children whose CD4+ T-lymphocyte counts have increased in response to HAART has not been studied.

Pregnant Women

(10) Chemoprophylaxis for MAC disease should be administered to pregnant women as is done for other adults and adolescents (AIII). However, because of general concerns about administering drugs during the first trimester of pregnancy, some providers may choose to withhold prophylaxis during the first trimester. Animal studies and anecdotal evidence of safety in humans suggest that of the available agents, azithromycin is the drug of choice (BIII) (49). Experience with rifabutin is limited. Clarithromycin has been demonstrated to be a teratogen in animals and should be used with caution during pregnancy (50). For secondary prophylaxis (chronic maintenance therapy), azithromycin plus ethambutol are the preferred drugs (BIII).

Prevention of Exposure

(1) Because Streptococcus pneumoniae and Haemophilus influenzae are common in the community, no effective way exists to reduce exposure to these bacteria.

Prevention of Disease

(2) As soon as feasible after HIV infection is diagnosed, adults and adolescents who have a CD4+ T-lymphocyte count of ≥ 200 cells/µL should be administered a single dose of 23-valent polysaccharide pneumococcal vaccine if they have not had this vaccine during the previous 5 years (BII) (5152). For persons who have a CD4+ T-lymphocyte count of <200 cells/µL, vaccination can be offered, although the humoral response and clinical efficacy are likely to be diminished (CIII). The recommendation to vaccinate is increasingly pertinent because of the increasing incidence of invasive infections with drug-resistant (including TMP-SMZ-, macrolide-, penicillin-, and β-lactam-resistant) strains of S. pneumoniae. Limited data suggest that administration of certain bacterial vaccines might transiently increase HIV replication and plasma HIV-1 RNA levels in a minority of HIV-infected persons. However, there is no evidence that adverse clinical outcomes are associated with this transient increase. Most experts believe that the benefit of pneumococcal vaccination outweighs the potential risk.

(3) The duration of the protective effect of primary pneumococcal vaccination is unknown. Periodic revaccination may be considered; an interval of 5 years has been recommended for persons not infected with HIV and also might be appropriate for persons infected with HIV (53). In addition, revaccination one time should also be considered if the initial vaccination was given when the CD4+ T-lymphocyte count was <200 cells/µL and if the CD4+ T-lymphocyte count has increased to >200 cells/µL as a result of HAART (CIII).

(4) The incidence of H. influenzae type B infection in adults is low. Therefore, H. influenzae type B vaccine is not generally recommended for adult use (DIII).