2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus.

In 1995, the US 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)1–3. These guidelines, written for health-care providers and patients, were revised in 19974 and again in 19995. They have been published in the MMWR1,4,5, Clinical Infectious Diseases2,6,7, the Annals of Internal Medicine3,8, the American Family Physician9,10, and Pediatrics11; accompanying editorials have appeared in JAMA12,13. Response to these guidelines (e.g., the many requests for reprints, numerous web site contacts and observations from health-care providers) suggests they have served as a valuable reference for HIV care providers. Because the 1995, 1997 and 1999 guidelines included ratings indicating the strength of each recommendation and the quality of supporting evidence, readers have been able to assess the relative importance of each recommendation. Since AIDS was first recognized 20 years ago, remarkable progress has been made in improving the quality and duration of life of HIV-infected persons in the industrialized world. 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 important opportunistic pathogens. The second decade of the epidemic has witnessed extraordinary progress in developing highly active antiretroviral therapies (HAART) as well as continuing progress in preventing and treating individual OIs. HAART has reduced the incidence of OIs and extended life substantially14–16. HAART is the most effective approach to preventing OIs and should be considered for all HIV-infected persons who qualify for such therapy14–16. 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 OIs15. In addition, prophylaxis against specific OIs continues to provide survival benefits even among persons who are receiving HAART15. Since HAART was introduced in the United States in 1995, it has become increasingly clear that chemoprophylaxis for OIs need not necessarily be life-long. Antiretroviral therapy can restore immune function. The period of susceptibility to opportunistic processes continues to be accurately indicated by the CD4+ T lymphocyte count for patients who are receiving HAART. Thus, a strategy of stopping primary or secondary prophylaxis for certain patients whose immunity has improved as a consequence of HAART seems logical. Stopping prophylactic regimens can simplify treatment, reduce toxicity and drug interactions, lower cost of care and potentially facilitate adherence to antiretroviral regimens. Infect Dis Obstet Gynecol 2002;10:3–64


INTRODUCTION
In 1995, the US 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) [1][2][3] . These guidelines, written for health-care providers and patients, were revised in 1997 4 and again in 1999 5 . They have been published in the MMWR 1,4,5 , Clinical Infectious Diseases 2,6,7 , the Annals of Internal Medicine 3,8 , the American Family Physician 9,10 , and Pediatrics 11 ; accompanying editorials have appeared in JAMA 12,13 . Response to these guidelines (e.g., the many requests for reprints, numerous web site contacts and observations from health-care providers) suggests they have served as a valuable reference for HIV care providers. Because the 1995, 1997 and 1999 guidelines included ratings indicating the strength of each recommendation and the quality of supporting evidence, readers have been able to assess the relative importance of each recommendation.
Since AIDS was first recognized 20 years ago, remarkable progress has been made in improving the quality and duration of life of HIV-infected persons in the industrialized world. 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 important opportunistic pathogens. The second decade of the epidemic has witnessed extraordinary progress in developing highly active antiretroviral therapies (HAART) as well as continuing progress in preventing and treating individual OIs. HAART has reduced the incidence of OIs and extended life substantially [14][15][16] . HAART is the most effective approach to preventing OIs and should be considered for all HIV-infected persons who qualify for such therapy [14][15][16] . 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 15 . In addition, prophylaxis against specific OIs continues to provide survival benefits even among persons who are receiving HAART 15 .
Since HAART was introduced in the United States in 1995, it has become increasingly clear that chemoprophylaxis for OIs need not necessarily be life-long. Antiretroviral therapy can restore immune function. The period of susceptibility to opportunistic processes continues to be accurately indicated by the CD4 + T lymphocyte count for patients who are receiving HAART. Thus, a strategy of stopping primary or secondary prophylaxis for certain patients whose immunity has improved as a consequence of HAART seems logical. Stopping prophylactic regimens can simplify treatment, reduce toxicity and drug interactions, lower cost of care and potentially facilitate adherence to antiretroviral regimens. Infect Dis Obstet Gynecol 2002;10:3-64 In 1999, the USPHS/IDSA guidelines suggested that it may be safe to stop primary or secondary prophylaxis for some (but not all) pathogens if HAART has led to an increase in CD4 + T lymphocyte counts above specified threshold levels. Recommendations were made for only those pathogens for which adequate clinical data were available. Data generated since 1999 continue to support these recommendations and allow additional recommendations to be made concerning the safety of stopping primary or secondary prophylaxis for other pathogens.
For recommendations on discontinuation of chemoprophylaxis, readers will note that criteria vary by such factors as duration of CD4 + T lymphocyte count increase, and, in the case of secondary prophylaxis, duration of treatment of the initial episode of disease. These differences reflect the criteria used in specific studies. Therefore, some inconsistency in the format of these criteria is unavoidable.
Although considerable data are now available concerning discontinuing primary and secondary OI prophylaxis, essentially no data are available regarding restarting prophylaxis when the CD4 + T lymphocyte count decreases again to levels at which the patient is likely to again be at risk for OI. For primary prophylaxis, whether to use the same threshold at which prophylaxis may be stopped (derived from data in studies addressing prophylaxis discontinuation), or to use the threshold below which initial prophylaxis is recommended is unknown. Therefore in this revision of the guidelines, in some cases ranges are provided for restarting primary or secondary prophylaxis. For prophylaxis against Pneumocystis carinii pneumonia (PCP), the suggested threshold for restarting both primary and secondary prophylaxis is 200 cells/ml. For all these recommendations, the roman numeral ratings reflect the lack of data available to assist in making these decisions (see description of rating system below).
During the development of these revised guidelines, working group members reviewed published manuscripts as well as abstracts and material presented at professional meetings. A series of teleconferences were held to develop the revisions. In this revision, information and recommendations which are new since the 1999 publication are indicated in bold.

MAJOR CHANGES IN THESE RECOMMENDATIONS
Major changes in the guidelines since 1999 include:

Additional information about transmission of human herpes virus 8 infection (HHV-8) is provided.
7. New information on drug interactions is provided, especially with regard to rifamycins and antiretroviral drugs. 8. Revised recommendations for immunization of HIV exposed/infected adults and children are provided.

HOW TO USE THE INFORMATION IN THIS REPORT
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 17 . In this system, the letters A-E signify the strength of the recommendation for or against a preventive measure and roman numerals I-III indicate the quality of evidence supporting the recommendation (see Table 1). This report incldes a number of tables that summarize recommendations. They are as follows: 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

III
Both strong evidence for efficacy and substantial clinical benefit support recommendation for use. Should always be offered Moderate evidence for efficacy -or strong evidence for efficacy but only limited clinical benefit -supports recommendation for use. Should generally be offered Evidence for efficacy is insufficient to support a recommendation for or against use. Or evidence for efficacy might not outweigh adverse consequences (e.g.,drug toxicity, drug, interactions) or cost of the chemoprophylaxis or alternative approaches. Optional Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should generally not be offered Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should never be offered Quality of evidence supporting the recommendation Evidence from at least one properly randomized, controlled trial Evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than one center), or from multiple time-series studies. Or dramatic results from uncontrolled experiments Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees    (Table 10); immunization schedule for HIV-infected children (Table 11); dosages for prophylaxis to prevent first episode of opportunistic disease in HIV-infected infants and children (Table 12); dosages for prophylaxis to prevent recurrence of opportunistic disease in HIV-infected infants and children (Table 13); and criteria for discontinuing and restarting OI prophylaxis for adult patients with HIV infection  1 Pyrimethamine-sulfadiazine confers protection against PCP as well as toxoplasmosis; clindamycin-pyrimethamine does not offer protection against PCP. 2 Many multiple-drug regimens are poorly tolerated. Drug interactions (e.g., those seen with clarithromycin and rifabutin) can be problematic; rifabutin has been associated with uveitis, especially when administered at daily doses of > 300 mg or concurrently with fluconazole or clarithromycin. See discussion of rifamycin interactions in paragraph 9 in section on Tuberculosis (54). 3 Efficacy for eradication of Salmonella has been demonstrated only for ciprofloxacin. *During pregnancy, azithromycin is recommended instead of clarithromycin because clarithromycin is teratogenic in animals.    (Table 14). Recommendations advising patients how to prevent exposure to opportunistic pathogens appear in the Appendix at the end of this report. 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 HAART, which is designed to prevent immunologic deterioration, to restore immune function and delay the need for many of the chemoprophylactic strategies described in this report, were originally published elsewhere 14 and are updated regularly (www.hivatis.org) 16 .
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 review emerging data routinely and will update these guidelines on a regular basis.

PNEUMOCYSTIS CARINII PNEUMONIA Prevention of exposure
Although some authorities recommend that persons with HIV infection who are at risk for P. carinii pneumonia (PCP) not share a hospital room with a patient who has PCP, data are insufficient to support this recommendation as standard practice (CIII).

Initiation of primary prophylaxis
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 less than 200 ml (AI) or a history of oropharyngeal candidiasis (AII) [18][19][20] . Persons who have a CD4 + T lymphocyte percentage of less than 14% or history of an acquired immunodeficiency syndrome (AIDS)-defining illness but do not otherwise qualify should be considered for prophylaxis (BII) [18][19][20] . 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 greater than 200 but less than 250 cells/ml also should be considered (BII) 19 .  Trimethoprim-sulfamethoxazole (TMP-SMZ) is the recommended prophylactic agent (AI) [20][21][22][23] . One double-strength tablet per day is the preferred regimen (AI) 23 . However, one single-strength tablet per day is also effective and might be better tolerated than one double strength tablet per day (AI). One double-strength tablet three times per week is also effective (BI) 24 . TMP-SMZ at a dose of one double-strength tablet per day confers cross-protection against toxoplasmosis 25 and some common respiratory bacterial infections 21,26 . 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 INFECTIOUS  Clinical significance unknown; monitor for ddI-related adverse effects *Little data are available for use of rifamycin drugs with ritonavir-boosting protease inhibitor regimens except for ritonavir-saquinavir and ritonavir-lopinavir. Therefore, concomitant use of rifamycins with these regimens must be approached cautiously Table 6 Effects of opportunistic infection medications on antiinfective drugs commonly administered to persons infected with human immunodeficiency virus* 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) 27,28 or reintroduction of TMP-SMZ at a reduced dose or frequency (CIII); up to 70% of patients can tolerate such reinstitution of therapy 26 .
If TMP-SMZ cannot be tolerated, prophylactic regimens that can be recommended as alternatives include dapsone (BI) 21 , dapsone plus pyrimethamine plus leucovorin (BI) 29,30 , aerosolized pentamidine administered by the Respirgard II TM nebulizer (Marquest, Englewood, Colorado) (BI) 22 and atovaquone (BI) 31,32 . Atovaquone appears to be as effective as aerosolized pentamidine 31 or dapsone (BI) 32 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) 29,30 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
Primary pneumocystis prophylaxis should be discontinued in adult and adolescent patients who have responded to HAART with an increase in CD4 + T lymphocyte counts to > 200 cells/ml for at least 3 months (AI). In observational and randomized studies supporting this recommendation, most patients were taking antiretroviral regimens that included a protease inhibitor and most had a CD4 + T lymphocyte count greater than 200 cells/ml for at least 3 months before discontinuation of PCP prophylaxis [33][34][35][36][37][38][39][40][41] . The median CD4 + lymphocyte count at the time prophylaxis was discontinued was > 300 cells/ml, and many patients had a sustained suppression of HIV plasma RNA levels below detection limits of the assay employed. Median follow-up ranged from 6-16 months.  Table 8 Dosing of drugs for primary prevention or maintenance therapy for opportunistic infections in renal insufficiency *Discontinuation of primary prophylaxis in these patients is recommended not only because prophylaxis appears to add very little to disease prevention (for PCP, toxoplasmosis, or bacterial infections), but also because discontinuation of drug reduces pill burden, the potential for drug toxicity, drug interactions, selection of drug-resistant pathogens and cost.

Restarting primary prophylaxis
Prophylaxis should be reintroduced if the CD4 + T lymphocyte count decreases to < 200 cells/ml (AIII).

Prevention of recurrence
Patients who have a history of PCP should be administered chemoprophylaxis (i.e., secondary prophylaxis or chronic maintenance therapy) with the regimens listed in Table 3 for life (AI) unless immune reconstitution occurs as a consequence of HAART.

Discontinuation of secondary prophylaxis (Chronic maintenance therapy (CMT))
Secondary prophylaxis should be discontinued for adult and adolescent patients whose CD4 + T cell count has increased from < 200 cells ml to > 200 cells/ml for at least 3 months due to HAART (BII). Reports from observational studies 37,41,42 and from a randomized trial 39 , as well as a combined analysis of eight European cohorts being followed prospectively 43 , support this recommendation. In these studies, patients had responded to HAART with an increase in CD4 + T lymphocyte count to > 200 cells/ml for at least 3 months. Most patients were taking protease inhibitor-containing regimens. The median CD4 + T lymphocyte count at the time prophylaxis was discontinued was > 300 cells/ml. Most patients had sustained suppression of HIV plasma HIV RNA levels below the detection limits of the assay employed; the longest follow-up was 13 months. If the episode of PCP occurred at a CD4 + T lymphocyte count > 200 cells/ml, it   Table 9 Wholesale acquisition costs of agents recommended for the prevention of opportunistic infections in adults infected with human immunodeficiency virus is probably prudent to continue PCP prophylaxis for life regardless of how high the CD4+ T lymphocyte count rises as a consequence of HAART (CIII). Discontinuation of secondary prophylaxis for patients is recommended (see above*).

Children
Children born to HIV-infected mothers should be administered prophylaxis with TMP-SMZ beginning at 4-6 weeks of age 44 (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 12) (AII). The safety of discontinuing prophylaxis in HIV-infected children receiving HAART has not been studied extensively. Children who have a history of PCP should be administered lifelong chemoprophylaxis to prevent recurrence 44 (AI).

Pregnant women
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).

TOXOPLASMIC ENCEPHALITIS Prevention of exposure
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).  Table 10 Immunologic categories for human immunodeficiency virus-infected children based on age-specific CD4 + T lymphocyte counts and percentage of total lymphocytes* This schedule indicates the recommended ages for routine administration of currently licensed childhood vaccines as of November 1, 2000, for children through age 18 years. Additional vaccines may be licensed and recommended during the year. Licensed combination vaccines may be used whenever any components of the combination are indicated and the vaccine's other components are not contraindicated. Providers should consult the manufacturer's package inserts for detailed recommendations. 1. Infants born to hepatitis B surface antigen (HBsAg)-negative mothers should receive the first dose of hepatitis B vaccine (Hep B) at birth and no later than age 2 months. The second dose should be administered at least 1 month after the first dose. The third dose should be administered at least 4 months after the first dose and at least 2 months after the second dose, but not before age 6 months. Infants born to HBsAg-positive mothers should receive Hep B and 0.5 ml hepatitis B immune globulin (HBIG) within 12 hours of birth at separate sites. The second dose is recommended at age 1-2 months and the third dose at age 6 months. Infants born to mothers whose HBsAg status is unknown should receive Hep B within 12 hours of birth. Maternal blood should be drawn at delivery to determine the mother's HBsAg status; if the HBsAg test is positive, the infant should receive HIBG as soon as possible (no later than age one week). All children and adolescents (through age 18 years) who have not been immunized against hepatitis B should begin the series during any visit. Providers should make special efforts to immunize children who were born in or whose parents were born in areas of the world where hepatitis B virus infection is moderately or highly endemic. 2. The fourth dose of diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) may be administered as early as age 12 months, provided 6 months have elapsed since the third dose and the child is unlikely to return at age 15-18 months. Tetanus and diphtheria toxoids (Td) is recommended at age 11-12 years if at least 5 years have elapsed since the last dose of diphtheria and tetanus toxoids and pertussis ) is administered at ages 2 and 4 months, a dose at age 6 months is not required. Because clinical studies in infants have demonstrated that using some combination products may induce a lower immune response to the Hib vaccine component, DTaP/Hib combination products should not be used for primary immunization in infants at ages 2, 4 or 6 months unless approved by the Food and Drug Administration for these ages.
4. An all-inactivated poliovirus vaccine (IPV) schedule is recommended for routine childhood polio vaccination in the United States. All children should receive four doses of IPV at age 2 months, age 4 months, between ages 6 and 18 months, and between ages 4 and 6 years. Oral poliovirus vaccine should not be administered to HIV infected persons or their household contacts. 5. Hepatitis A vaccine (Hep A) is recommended for use in selected states and/or regions, and for certain high-risk groups such as those with Hepatitis B or Hepatitis C infection. Information is available from local public health authorities. 6. The heptavalent pneumococcal conjugate vaccine (PCV) is recommended for all children age 2-59 months with HIV. Children 2 years and older should also receive the 23 valent pneumococcal polysaccharide vaccine; a single revaccination with the 23 valent vaccine should be offered to children after 3-5 years. Refer to the Advisory Committee on Immunization Practices recommendations (80) on dosing intervals for children starting the vaccination schedule after 2 months of age. 7. MMR should not be administered to severely immunocompromisd (category 3) children. HIV infected children without severe immunosuppression would routinely receive their first dose of MMR as soon as possible after reaching their first birthday. Consideration should be given to administering the second dose of MMR as soon as 1 month (i.e., a minimum of 28 days) after the first dose rather than waiting until school entry. 8. Varicella zoster virus vaccine, 0.5 ml, is given as a subcutaneous dose between 12 months and 12 years of age; a second dose should be given 3 months later. The vaccine should be given only to asymptomatic, nonimmunosuppressed children. 9. For children aged 6 months to < 9 years who are receiving influenze vaccine for the first time, two injections given one month apart are recommended. For specific recommendations, see: CDC, Prevention and Control of Influenza:  HIV exposure/infection Routine immunizations (see Table 10)

Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2001;50:RR-4. Inactivated split influenza virus vaccine should be administered to all HIV infected children 6 months of age each year
None

III. Not recommended for most children; indicated for use only in unusual circumstances
Invasive bacterial infections 6 Hypogamma-globulinemia (i.e., IgG < 400 mg/dl) The efficacy of parenteral pentamidine (e.g. 4 mg/kg q 2-4 wks) is controversial. Patients receiving therapy for toxoplasmosis with sulfadiazine-pyrimethamine are protected against PCP and do not need TMP-SMZ. 2 Significant drug interactions might occur between rifamycins (rifampin and rifabutin) and protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Consult a specialist. 3 Children routinely being administered intravenous immune globulin (IVIG) should receive VZIG if the last dose of IVIG was administered > 21 days before exposure. 4 HIV-infected and HIV-exposed children should be immunized according to the childhood immunization schedule in this report (Table 10), which has been adapted from the January-December 2001 schedule recommended for immunocompetent children by the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the American Academy of Family Physicians. This schedule differs from that for immunocompetent children in that both the conjugate pneumococcal vaccine (PCV-7) and the pneumococcal polysaccharide vaccine (PPV-23) are recommended (BII) and vaccination against influenza (BIII) should be offered. MMR should not be administered to severely immunocompromised children (DIII). Vaccination against varicella is indicated only for asymptomatic nonimmunosuppressed children (BII). Once an HIV-exposed child is determined not to be HIV infected, the schedule for immunocompetent children applies. 5 Protection against toxoplasmosis is provided by the preferred antipneumocystis regimens and possibly by atovaquone. Atovaquone may be used with or without pyrimethamine. Pyrimethamine alone probably provides little, if any, protection (for definition of severe immunosuppression, see Table 9). 6 Respiratory syncytial virus (RSV) IVIG (750 mg/kg), not monoclonal RSV antibody, may be substituted for IVIG during the RSV season to provide broad antiinfective protection, if this product is available. 7 Oral ganciclovir and perhaps valganciclovir results in reduced CMV shedding in CMV-infected children. Acyclovir is not protective against CMV  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 lamb, beef, pork or venison (BIII). Specifically, lamb, beef and pork should be cooked to an internal temperature of 165-170 F 44 ; meat cooked until it is no longer pink inside generally has an internal temperature of 165-170 F and therefore from a more practical perspective, 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). INFECTIOUS 1 Only pyrimethamine plus sulfadiazine confers protection against PCP as well as toxoplasmosis. Although the clindamycin plus pyrimethamine regimen is recommended in adults, it has not been tested in children. However, these drugs are safe and are used for other infections. 2 Significant drug interactions might occur between rifabutin and protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Consult an expert. 3 Drug should be determined by susceptibilities of the organism isolated. Alternatives to TMP-SMZ include ampicillin, chloramphenicol, or ciprofloxacin. However, ciprofloxacin is not approved for use in persons aged < 18 years; therefore, it should be used in children with caution and only if no alternatives exist. 4 Antimicrobial prophylaxis should be chosen based on the microorganism and antibiotic sensitivities. TMP-SMZ, if used, should be administered daily. Providers should be cautious about using antibiotics solely for this purpose because of the potential for development of drug-resistant microorganisms. IVIG might not provide additional benefit to children receiving daily TMP-SMZ but may be considered for children who have recurrent bacterial infections despite TMP-SMZ prophylaxis. Choice of antibiotic prophylaxis vs. IVIG should also involve consideration of adherence, ease of intravenous access, and cost, if IVIG is used, respiratory syncytial virus (RSV) IVIG (750 mg/kg), not monoclonal RSV antibody, may be substituted for IVIG during the RSV season to provide broad anti-infective protection, if this product is available

Initiation of primary prophylaxis
Toxoplasma-seropositive patients who have a CD4 + T lymphocyte count of less than 100/ml should be administered prophylaxis against toxoplasmic encephalitis (TE) (AII) 25 . 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) 25 . If patients cannot tolerate TMP-SMZ, the recommended alternative is dapsone-pyrimethamine, which is also effective against PCP (BI) 29,30 . 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) 21,25 .
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/ml 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).

Prophylaxis against TE should be discontinued in adult and adolescent patients who have responded to HAART with an increase in CD4 + T lymphocyte counts to > 200 cells/ml for at least 3 months (AI).
Several observational studies 37,41,47 and two randomized trials 38,46 have shown that primary prophylaxis can be discontinued with minimal risk of developing TE in patients who have responded to HAART with an increase in CD4 + T lymphocyte count from < 200 cells/ml to > 200 cells/ml for at least 3 months. In these studies, most patients were taking protease inhibitor-containing regimens and the median CD4 + T lymphocyte count at the time prophylaxis was discontinued was > 300 cells/ml. At the time prophylaxis was discontinued, many patients had sustained suppression of plasma HIV RNA levels below the detection limits of available assays; the median follow up ranged from 7-22 months.
While patients with CD4 + T lymphocyte counts of < 100 cells/ml are at greatest risk for developing TE, the risk of TE occurring when the CD4 + T lymphocyte count has increased to 100-200 cells/ml has not been studied as rigorously as a rise to > 200 cells/ml. Thus, the recommendation specifies discontinuation of prophylaxis after an increase to > 200 cells/ml. Discontinuation of primary TE prophylaxis is recommended not only because prophylaxis appears to add very little to disease prevention for toxoplasmosis, but also because discontinuation of drug reduces pill burden, the potential for drug toxicity, drug interaction and selection of drug resistant pathogens.

Prevention of recurrence
Patients who have completed initial therapy for TE should be administered lifelong suppressive therapy (secondary prophylaxis or CMT) (AI) 48,49 unless immune reconstitution occurs as a consequence of HAART (see below). The combination of pyrimethamine plus sulfadiazine plus leucovorin is highly effective for this purpose (AI). 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 (CMT)
Adult and adolescent patients receiving secondary prophylaxis (CMT) for TE 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 increase in their CD4 + T lymphocyte counts to > 200 cells/ml following HAART (e.g., 6 months) 41,42,46 . While the numbers of patients who have been evaluated remain small and occasional recurrences have been seen, based on these observations and on inference from more extensive cumulative data suggesting the safety of discontinuation of secondary prophylaxis for other OIs during advanced HIV disease, it is reasonable to consider discontinuation of CMT in such patients (CIII). Some experts would obtain a magnetic resonance image of the brain as part of their evaluation to determine whether or not discontinuation of therapy is appropriate.

Special considerations
Children TMP-SMZ, when administered for PCP prophylaxis, also provides prophylaxis against toxoplasmosis. Atovaquone might also provide protection (CIII). Children aged greater than 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).
Children with a history of toxoplasmosis should be administered lifelong prophylaxis to prevent recurrence (AI). The safety of discontinuing primary or secondary prophylaxis in HIV-infected children receiving HAART has not been studied extensively.

Pregnant Women
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. The above guidelines should be used when making decisions regarding secondary prophylaxis for TE in pregnancy.
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).

CRYPTOSPORIDIOSIS
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 less than six months, and should not adopt stray pets. HIV-infected persons who wish to assume the small risk for acquiring a puppy or kitten aged less than six 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, 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* (home/office types) and/or bottled water** also might reduce the risk (CIII). The magnitude of the risk for acquiring cryptosporidiosis from drinking water in a non-outbreak 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 non-carbonated 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 pasterurized 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 food-borne 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. Rifabutin or clarithromycin, when taken for Mycobacterium avium complex prophylaxis, have been found to protect against cryptosporidiosis 50,51 . However, data are insufficient at this time to warrant a recommendation for using these drugs as chemoprophylaxis for cryptosporidiosis.
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). 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 TB in the community and the degree to which precautions are taken to prevent the transmission of TB in the workplace (BIII). Whether the patient continues with such activities might affect the frequency with which screening for TB needs to be conducted. Options include isoniazid daily (AII) or twice weekly (BII) for nine months; four months of therapy daily with either rifampin (BIII) or rifabutin (CIII); or two months of therapy with either rifampin and pyrazinamide (BI) or rifabutin and pyrazinamide (CIII) [52][53][54] . There have been reports of fatal and severe liver injury associated with the treatment of latent TB infection in HIV-uninfected persons treated with the two-month regimen of daily rifampin and pyrazinamide; therefore it may be prudent to use regimens that do not contain pyrazinamide in HIV-infected persons whose completion of treatment can be assured 55 . 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 *Only filters capable of removing particles 1 mm 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 mm filters, and those labeled as meeting NSF (National Sanitation Foundation) standard no. 53 for cyst removal. The nominal 1 mm filter rating is not standardized, and many filters in this category might not be capable of removing 99% of oocysts. For a list of filters certified as meeting NSF standards, consult the International Consumer Line at 800-673-8010 or http://www.nsf.org/notice/crypto.html **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 mm 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 mm filters by bottlers as the only barrier to Cryptosporidia might not result in the removal of 99% of oocysts. For more information, the International Bottled Water Association can be contacted at 703-683-5213 or at http://bottled water.org made after careful consideration of potential drug interactions, especially those related to protease inhibitors and nonnucleoside reverse transcriptase inhibitors (see Special Considerations/Drug Interactions). Directly observed therapy should be used with intermittent dosing regimens (AI) and when otherwise operationally feasible (BIII) 53 . 5. HIV-infected persons who are close contacts of persons who have infectious TB should be treated for latent TB infection -regardless of their TST results, age or prior courses of treatment -after the diagnosis of active TB has been excluded (AII) [52][53][54] . In addition to household contacts, such persons might also include contacts in the same drug-treatment or health-care facility, co-workers and other contacts if transmission of TB is demonstrated. 6. For persons exposed to isoniazid-and/or rifampin-resistant TB, the decision to use chemoprophylactic antimycobacterial agents other than isoniazid alone, rifampin or rifabutin 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 treatment 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 should consider repeating the TST for persons whose initial skin test was negative and whose immune function has improved in response to HAART (i.e., those whose CD4 + T lymphocyte count has increased to greater than 200 cells/ml) (BIII) 52 . In addition to confirming TB 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-Guerin (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). 53 . However, it may be used with ritonavir, ritonavir plus saquinavir, efavirenz and possibly with nevirapine. Rifabutin is an acceptable alternative to rifampin but should not be used with the protease inhibitor hard-gel saquinavir or delavirdine; caution is advised if the drug is coadministered with soft-gel saquinavir, because data are sparse. 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, ritonavir plus saquinavir, or lopinavir/ritonavir.

When rifabutin is administered with indinavir as the sole protease inhibitor, the dose of indinavir should be increased from 800 mg every 8 h to 1000 mg every 8 h. Pharmacokinetic data suggest that rifabutin at an increased dose can be administered with efavirenz; doses of 450-600 mg per day have been suggested 54 . However, little information is available about appropriate dosing if a protease inhibitor is used concurrently with efavirenz and rifabutin; with such a combination the rifabutin dose might need to be reduced. Rifabutin can be used without dose adjustment 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 TB (AIII); children exposed to a person who has active TB should be administered preventive therapy after active TB has been excluded, regardless of their TST results (AII).

Pregnant women
13. Chemoprophylaxis for TB is recommended during pregnancy for HIV-infected patients who have either a positive TST or a history of exposure to active TB, after active TB 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 TB, 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.

DISSEMINATED INFECTION WITH MYCOBACTERIUM AVIUM COMPLEX
Prevention of exposure 1. Organisms of the M. avium complex (MAC) are common in environmental sources such as food and water. Current information does not support specific recommendations regarding avoidance of exposure.

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 less than 50 cells/ml (AI) 56 . Clarithromycin 57,58 or azithromycin 59 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) 59 . 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) 59 . 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 although rifabutin-associated drug interactions make this agent difficult to use (BI) 54 . 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). 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 TB, active TB 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).

Primary prophylaxis should be reintroduced if the CD4 + T lymphocyte count decreases to < 50-100 cells/ml (AIII).
Prevention of recurrence 63,64 . 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) 65,66 . Clofazimine has been associated with adverse clinical outcomes in the treatment of MAC disease and should not be used (DII) 66 .

Discontinuation of secondary prophylaxis (CMT)
7. Patients appear to be at low risk for recurrence of MAC when they have completed a course of at least 12 months of treatment for MAC, remain asymptomatic with respect to MAC signs and symptoms, and have a sustained increase , e.g., six months, in their CD4 + T lymphocyte counts to > 100 cells/ml following HAART. While the numbers of patients who have been evaluated remain small, and recurrences could occur 41,42,68-70 , based on these observations and on inference from more extensive data suggesting the safety of discontinuation of secondary prophylaxis for other OIs during advanced HIV disease, it may be reasonable to consider discontinuation of CMT in such patients (CIII). Some experts would obtain a blood culture for MAC, even in asymptomatic patients, prior to discontinuation of therapy, to substantiate that disease is no longer active.

Rifabutin should not be administered to patients receiving certain protease inhibitors and nonnucleoside reverse transcriptase inhibitors because the complex interactions have been incompletely studied and the clinical implications of those interactions are unclear 16,54 (see Special Considerations: Drug interactions in the Tuberculosis section, above). Protease inhibitors may increase clarithromycin levels, but no recommendation to adjust the dose of either clarithromycin or protease inhibitors can be made on the basis of existing data. Efavirenz can induce metabolism of clarithromycin. This may result in reduced serum concentration of clarithromycin but increased concentration of 14-OH clarithromycin, an active metabolite of clarithromycin. Although the clinical significance of this interaction is not known, the efficacy of clarithromycin in MAC prophylaxis could be reduced because of this interaction. Azithromycin pharmacokinetics are not affected by the cytochrome P450 system; azithromycin can be used safely in the presence of protease inhibitors and/or nonnucleoside reverse transcriptase inhibitors without concerns of drug interactions.
Children 10. HIV-infected children aged less than 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 greater than or equal to six years, less than 50 cells/ml; children aged 2-6 years, less than 75 cells/ml; children aged 1-2 years, less than 500 cells/ml; and children aged less than 12 months, less than 750 cells/ml (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. Children with a history of disseminated MAC should be administered lifelong prophylaxis to prevent recurrence (AII). The safety of discontinuing MAC prophylaxis in children whose CD4 + T lymphocyte counts have increased in response to HAART has not been studied. 11. 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) 71 . Experience with rifabutin is limited. Clarithromycin has been demonstrated to be a teratogen in animals and should be used with caution during pregnancy 72 . For secondary prophylaxis (CMT), azithromycin plus ethambutol are the preferred drugs (BIII) 70 .

BACTERIAL RESPIRATORY INFECTIONS
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.

Adults and adolescents who have a CD4 + T lymphocyte count of greater than or equal to 200 cells/ml should be administered a single dose of 23-valent polysaccharide pneumococcal vaccine if they have not received this vaccine during the previous five years (BII) 73-77 . One randomized placebo-controlled trial of pneumococcal vaccine in Africa paradoxically found an increase in pneumonia among vaccinated subjects 78 . However, several observational studies in the United States have not identified increased risk associated with vaccination and have identified benefit in this group 73-77 . Most experts believe that the potential benefit of pneumococcal vaccination in the United States outweighs the risk. Immunization should also be considered for patients with CD4 + T lymphocyte counts < 200 cells/ml, although there is no clinical evidence for efficacy (CIII). Revaccination may be considered for patients who were initially immunized when their CD4 + T lymphocyte count was < 200 cells/ml and whose CD4 + count has increased to > 200 cells/ml in response to HAART (CIII). The recommendation to vaccinate is increasingly pertinent because of the increasing incidence of invasive infections with drug-resistant (including TMP-SMZ-, macrolide-and beta-lactam-resistant) strains of S. pneumoniae.
3. The duration of the protective effect of primary pneumococcal vaccination is unknown. Periodic revaccination may be considered; an interval of five years has been recommended for persons not infected with HIV and also might be appropriate for persons infected with HIV (CIII) 76 . There is, however, no evidence for clinical benefit from revaccination. 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). 5. TMP-SMZ, when administered daily for PCP prophylaxis, reduces the frequency of bacterial respiratory infections. This should be considered in the selection of an agent for PCP prophylaxis (AII). However, indiscriminate use of this drug (when not indicated for PCP prophylaxis or other specific reasons) might promote the development of TMP-SMZ-resistant organisms. Thus, TMP-SMZ should not be prescribed solely to prevent bacterial respiratory infection (DIII). Similarly, clarithromycin administered daily and azithromycin administered weekly for MAC prophylaxis might be effective in preventing bacterial respiratory infections; this should be considered in the selection of an agent for prophylaxis against MAC disease (BII). However, these drugs should not be prescribed solely for preventing bacterial respiratory infection (DIII).
6. An absolute neutrophil count that is depressed because of HIV disease or drug therapy is associated with an increased risk for bacterial infections, including pneumonia. To reduce the risk for such bacterial infections, providers may consider taking steps to reverse neutropenia, either by stopping myelosuppressive drugs (CII) or by administering granulocyte-colony-stimulating factor (G-CSF) (CII).
Prevention of recurrence 7. Some clinicians may administer antibiotic chemoprophylaxis to HIV-infected patients who have very frequent recurrences of serious bacterial respiratory infections (CIII). TMP-SMZ, administered for PCP prophylaxis and clarithromycin or azithromycin, administered for MAC prophylaxis, are appropriate for drug-sensitive organisms. However, providers should be cautious about using antibiotics solely for preventing the recurrence of serious bacterial respiratory infections because of the potential development of drug-resistant microorganisms and drug toxicity.

HIV infected children, less than five years old should be administered H. influenzae type B vaccine (AII) and pneumococcal conjugate vaccine 77-81 (BII) in accordance with the guidelines of the Advisory Committee on Immunization Practices 74,76,79 and the American Academy of Pediatrics 80 . Children aged greater than two years should also receive the 23-valent polysaccharide pneumococcal vaccine (BII). Revaccination with a second dose of the 23 valent polysaccharide pneumococcal vaccine should generally be offered after 3-5 years to children aged less than or equal to ten years and after five years to children aged greater than ten years (BIII).
9. To prevent serious bacterial infections in HIV-infected children who have hypogammaglobulinemia (IgG less than 400 mg/dl), clinicians should use intravenous (i.v.) immunoglobulin (IVIG) (AI). Respiratory syncytial virus (RSV) IVIG (750 mg/kg), not monoclonal RSV antibody, may be substituted for IVIG during the RSV season to provide broad anti-infective protection, if RSV IVIG is available. 10. To prevent recurrence of serious bacterial respiratory infections, antibiotic chemoprophylaxis may be considered (BI). However, providers should be cautious about using antibiotics solely for this purpose because of the potential development of drug-resistant microorganisms and drug toxicity. The administration of IVIG should also be considered for HIV-infected children who have recurrent serious bacterial infections, although such treatment might not provide additional benefit to children who are being administered daily TMP-SMZ. However, IVIG may be considered for children who have recurrent serious bacterial infections despite receiving TMP-SMZ or other antimicrobials (CIII) 82 . 11. Pneumococcal vaccination is recommended during pregnancy for HIV-infected patients who have not been vaccinated during the previous five years (BIII). Among nonpregnant adults, vaccination has been associated with a transient burst of HIV replication. Whether the transient viremia can increase the risk for perinatal HIV transmission is unknown. Because of this concern, when feasible, vaccination may be deferred until after HAART has been initiated to prevent perinatal HIV transmission (CIII).

BACTERIAL ENTERIC INFECTIONS
Prevention of exposure Food 1. Health-care providers should advise HIV-infected persons not to eat raw or undercooked eggs (including foods that might contain raw eggs [e.g., some preparations of hollandaise sauce, Caesar and certain other salad dressings, some mayonnaises, uncooked cookie and cake batter, egg nog]); raw or undercooked poultry, meat, seafood (especially raw shellfish); unpasteurized dairy products; unpasteurized fruit juices; and raw seed sprouts (e.g., alfalfa sprouts, mung bean sprouts). Poultry and meat are safest when adequate cooking is confirmed with a thermometer (internal tempera-

ture of 180°F for poultry and 165°F for red meats). If a thermometer is not used, the risk of illness is decreased by consuming poultry and meat that have no trace of pink color. Color change of the meat (e.g., absence of pink) does not always correlate with internal temperature. (BIII). Produce should be washed thoroughly before being eaten (BIII).
2. Health-care providers should advise HIV-infected persons to avoid cross-contamination of foods. Uncooked meats, (including hot dogs) and their juices should not come into contact with other foods. Hands, cutting boards, counters, knives, and other utensils should be washed thoroughly after contact with uncooked foods (BIII). 3. Health-care providers should advise HIV-infected persons that, although the incidence of listeriosis is low, it is a serious disease that occurs with unusually high frequency among severely immunosuppressed HIV-infected persons. An immunosuppressed, HIV-infected person who wishes to reduce the risk of acquiring listeriosis as much as possible may choose to do the following (CIII): a) avoid soft cheeses (e.g., feta, Brie, Camembert, blue-veined and Mexican-style cheese such as queso fresco).
Hard, processed and cream cheese (including slices and spreads), cottage cheese or yogurt need not be avoided; b) cook leftover foods or ready-to-eat foods (e.g., hot dogs) until steaming hot before eating; c) avoid foods from delicatessen counters (e.g., prepared salads, meats, cheeses) or heat/reheat these foods until steaming before eating; d) avoid refrigerated pates and other meat spreads, or heat/reheat these foods until steaming. Canned or shelf-stable pate and meat spreads need not be avoided and e) avoid raw or unpasteurized milk (including goat's milk) or milk-products, or foods which contain unpasteurized milk or milk-products. (CIII).

Pets
4. When obtaining a new pet, HIV-infected persons should avoid animals aged less than six months, especially those that have diarrhea (BIII). 5. HIV-infected persons should avoid contact with animals that have diarrhea (BIII). HIV-infected pet owners should seek veterinary care for animals with diarrheal illness, and a fecal sample from such animals should be examined for Cryptosporidium, Salmonella, and Campylobacter. 6. HIV-infected persons should wash their hands after handling pets (especially before eating) and should avoid contact with pets' feces (BIII). 7. HIV-infected persons should avoid contact with reptiles (e.g., snakes, lizards, iguanas and turtles) as well as chicks and ducklings because of the risk for salmonellosis (BIII). Travel 8. The risk for food-borne and waterborne infections among immunosuppressed, HIV-infected persons is magnified during travel to developing countries. Persons who travel to such countries should avoid foods and beverages that might be contaminated, particularly raw fruits and vegetables, raw or undercooked seafood or meat, tap water, ice made with tap water, unpasteurized milk and dairy products, and items sold by street vendors (AII). Foods and beverages that are generally safe include steaming-hot foods, fruits that are peeled by the traveler, bottled (especially carbonated) beverages, hot coffee and tea, beer, wine, and water brought to a rolling boil for 1 minute (AII). Treatment of water with iodine or chlorine might not be as effective as boiling but can be used when boiling is not practical (BIII).
Prevention of disease 9. Prophylactic antimicrobial agents are not generally recommended for travelers (DIII). The effectiveness of these agents depends on local antimicrobial-resistance patterns of gastrointestinal pathogens, which are seldom known. Moreover, these agents can elicit adverse reactions and can promote the emergence of resistant organisms. However, for HIV-infected travelers, antimicrobial prophylaxis may be considered, depending on the level of immunosuppression and the region and duration of travel (CIII). The use of fluoroquinolones such as ciprofloxacin (500 mg per day) can be considered when prophylaxis is deemed necessary (CIII). As an alternative (e.g., for children, pregnant women, and persons already taking TMP-SMZ for PCP prophylaxis), TMP-SMZ might offer some protection against traveler's diarrhea (BIII). The risk of toxicity should be considered before treatment with TMP-SMZ is initiated solely because of travel. 10. Antimicrobial agents such as fluoroquinolones should be given to patients before their departure, to be taken empirically (e.g., 500 mg of ciprofloxacin twice a day for 3-7 days) should significant traveler's diarrhea develop (BIII). Fluoroquinolones should be avoided for children aged less than 18 years and pregnant women, and alternative antibiotics should be considered (BIII). Travelers should consult a physician if their diarrhea is severe and does not respond to empirical therapy, if their stools contain blood, if fever is accompanied by shaking chills, or if dehydration develops. Antiperistaltic agents (e.g., loperamide) can be used to treat mild diarrhea. However, the use of these drugs should be discontinued if symptoms persist beyond 48 h. Moreover, these agents should not be administered to patients who have a high fever or who have blood in the stool (AII). 11. Some experts recommend that HIV-infected persons who have Salmonella gastroenteritis be administered antimicrobial therapy to prevent extraintestinal spread of the pathogen. However, no controlled study has demonstrated a beneficial effect of such treatment, and some studies of immunocompetent persons have suggested that antimicrobial therapy can lengthen the shedding period. The fluoroquinolones -primarily ciprofloxacin (750 mg twice a day for 14 days) -can be used when antimicrobial therapy is chosen (CIII).

Prevention of recurrence
12. HIV-infected persons who have Salmonella septicemia require long-term therapy (i.e., secondary prophylaxis or CMT) to prevent recurrence. Fluoroquinolones, primarily ciprofloxacin, are usually the drugs of choice for susceptible organisms (BII). 13. Household contacts of HIV-infected persons who have salmonellosis or shigellosis should be evaluated for persistent asymptomatic carriage of Salmonella or Shigella so that strict hygienic measures and/or antimicrobial therapy can be instituted and recurrent transmission to the HIV-infected person can be prevented (CIII).

Special considerations
Children 14. Like HIV-infected adults, HIV-infected children should wash their hands after handling pets (especially before eating) and should avoid contact with pets' feces. Hand washing should be supervised (BIII). 15. HIV-exposed infants aged less than three months and all HIV-infected children who have severe immunosuppression should be administered treatment for Salmonella gastroenteritis to prevent extraintestinal spread of the pathogen (CIII). Choices of antibiotics include TMP-SMZ, ampicillin, cefotaxime, ceftriaxone or chloramphenicol; fluoroquinolones should be used with caution and only if no alternatives exist. 16. HIV-infected children who have Salmonella septicemia should be offered long-term therapy to prevent recurrence (CIII). TMP-SMZ is the drug of choice; ampicillin or chloramphenicol can be used if the organism is susceptible. Fluoroquinolones should be used with caution and only if no alternative exists. 17. Antiperistaltic drugs are not recommended for children (DIII).

Pregnant women
18. Because both pregnancy and HIV infection confer a risk for listeriosis, pregnant HIV-infected women should heed recommendations regarding listeriosis (BII). 19. Because extraintestinal spread of Salmonella during pregnancy might lead to infection of the placenta and amniotic fluid and result in pregnancy loss similar to that seen with Listeria monocytogenes, pregnant women with Salmonella gastroenteritis should receive treatment (BIII). Choices for treatment include ampicillin, cefotaxime, ceftriaxone, or TMP-SMZ. Fluoroquinolones should be avoided. 20. Fluoroquinolones should not be used during pregnancy. TMP-SMZ might offer some protection against traveler's diarrhea.

BARTONELLOSIS
Prevention of exposure 1. HIV-infected persons, particularly those who are severely immunosuppressed, are at unusually high risk for developing relatively severe disease due to infection with Bartonella, which can be transmitted from cats. These persons should consider the potential risks of cat ownership (CIII). Persons who acquire a cat should adopt or purchase an animal aged greater than one year that is in good health (BII). Prevention of recurrence 6. Relapse or reinfection with Bartonella has sometimes followed a course of primary treatment. Although no firm recommendation can be made regarding prophylaxis in this situation, long-term suppression of infection with erythromycin or doxycycline should be considered (CIII).
Special considerations Children 7. The risks of cat ownership for HIV-infected children who are severely immunocompromised should be discussed with parents and caretakers (CIII).

Pregnant women
8. If long-term suppression of Bartonella infection is required, erythromycin should be used. Tetracycline should not be used during pregnancy.

CANDIDIASIS
Prevention of exposure 1. Candida organisms are common on mucosal surfaces and skin. No measures are available to reduce exposure to these fungi.
Prevention of disease 2. Data from prospective controlled trials indicate that fluconazole can reduce the risk for mucosal (oropharyngeal, esophageal and vaginal) candidiasis and cryptococcosis as well in patients with advanced HIV disease [76][77][78] . However, routine primary prophylaxis is not recommended because of the effectiveness of therapy for acute disease, the low mortality associated with mucosal candidiasis, the potential for resistant Candida organisms to develop, the possibility of drug interactions, and the cost of prophylaxis (DIII).

Prevention of recurrence
3. Many experts do not recommend chronic prophylaxis of recurrent oropharyngeal or vulvovaginal candidiasis for the same reasons that they do not recommend primary prophylaxis. However, if recurrences are frequent or severe, providers may consider administering an oral azole (fluconazole [CI] [83][84][85] or itraconazole solution [CI]). Other factors that influence choices about such therapy include the impact of the recurrences on the patient's well-being and quality of life, the need for prophylaxis for other fungal infections, cost, toxicities, drug interactions, and the potential to induce drug resistance among Candida and other fungi. Prolonged use of systemically absorbed azoles, particularly in patients with low CD4 + T lymphocyte counts (i.e., less than 100 cells/ml), increases the risk for the development of azole resistance. 4. Adults or adolescents who have a history of documented esophageal candidiasis, particularly multiple episodes, should be considered candidates for chronic suppressive therapy. Fluconazole at a dose of 100-200 mg daily is appropriate (BI). However, the potential development of azole resistance should be taken into account when long-term azoles are considered.

Special considerations
Children 5. Primary prophylaxis of candidiasis in HIV-infected infants is not indicated (DIII). 6. Suppressive therapy with systemic azoles should be considered for infants who have severe recurrent mucocutaneous candidiasis (CIII) and particularly for those who have esophageal candidiasis (BIII).

Pregnant women
7. Experience is limited with the use of systemic antifungal drugs during human pregnancy. Four cases of infants born with craniofacial and skeletal abnormalities following prolonged in utero exposure to fluconazole have been reported 86,87 . In addition, itraconazole is embryotoxic and teratogenic in animal systems 88 . These same potential risks of teratogenicity are presumed to apply to other systemically absorbed azole antifungals, such as ketoconazole. Therefore, chemoprophylaxis against oropharyngeal, esophageal, or vaginal candidiasis using systemically absorbed azoles should not be initiated during pregnancy (DIII), and azoles should be discontinued for HIV-infected women who become pregnant (DIII). Effective birth control measures should be recommended to all HIV-infected women on azole therapy for candidiasis (AIII).

CRYPTOCOCCOSIS
Prevention of exposure 1. HIV-infected persons cannot completely avoid exposure to Cryptococcus neoformans. No evidence exists that exposure to pigeon droppings is associated with an increased risk for acquiring cryptococcosis.
Prevention of disease 2. Routine testing of asymptomatic persons for serum cryptococcal antigen is not recommended because of the low probability that the results will affect clinical decisions (DIII). 3. Prospective controlled trials indicate that fluconazole and itraconazole can reduce the frequency of cryptococcal disease among patients who have advanced HIV disease. However, most experts recommend that antifungal prophylaxis not be used routinely to prevent cryptococcosis because of the relative infrequency of cryptococcal disease, the lack of survival benefits associated with prophylaxis, the possibility of drug interactions, the potential development of antifungal drug resistance, and cost. The need for prophylaxis or suppressive therapy for other fungal infections (e.g., candidiasis, histoplasmosis, or coccidioidomycosis) should be considered in making decisions about prophylaxis for cryptococcosis. If used, fluconazole at doses of 100-200 mg daily is reasonable for patients whose CD4 + T lymphocyte counts are less than 50 cells/ml (CI) 83 .
Prevention of recurrence 4. Patients who have completed initial therapy for cryptococcosis should be administered lifelong suppressive treatment, (i.e., secondary prophylaxis or CMT) (AI) unless immune reconstitution occurs as a consequence of HAART (see recommendation 5 below). Fluconazole is superior to itraconazole in preventing relapse of cryptococcal disease and is the preferred drug (AI) [89][90][91] .

Discontinuation of secondary prophylaxis (CMT)
5. Adult and adolescent patients appear to be at low risk for recurrence of cryptococcosis when they have successfully completed a course of initial therapy for cryptococcosis, remain asymptomatic with respect to signs and symptoms of cryptococcosis, and have a sustained increase (e.g., six months) in their CD4 + T lymphocyte counts to > 100-200 cells/ml following HAART. The numbers of patients who have been evaluated remain small 92,93 . Based on these observations and on inference from more extensive data suggesting the safety of discontinuation of secondary prophylaxis for other OIs during advanced HIV disease and while recurrences could occur it may be reasonable to consider discontinuation of CMT in such patients (CIII). Some experts would perform a lumbar puncture to determine if the CSF is culture negative before stopping therapy even if patients have been asymptomatic; other experts do not believe this is necessary.

Maintenance therapy should be reinitiated if the CD4 + T lymphocyte count decreases to 100-200 cells/ml (AIII).
Special considerations Children 7. No data exist on which to base specific recommendations for children, but lifelong suppressive therapy with fluconazole after an episode of cryptococcosis is appropriate (AIII).

Pregnant women
8. Prophylaxis with fluconazole or itraconazole should not be initiated during pregnancy because of the low incidence of cryptococcal disease, the lack of a recommendation for primary prophylaxis against cryptococcosis in nonpregnant adults, and potential teratogenic effects of these drugs during pregnancy (DIII) 86,87 . For patients who conceive while being administered primary prophylaxis and who elect to continue their pregnancy, prophylaxis should be discontinued. The occurrence of craniofacial and skeletal abnormalities in infants following prolonged in utero exposure to fluconazole should be considered when assessing the therapeutic options for HIV-infected women who become pregnant and are receiving secondary prophylaxis (CMT) for cryptococcosis 86,87 . If a woman meets the criteria for discontinuation of secondary prophylaxis as discussed above, strong consideration should be given to discontinuing therapy during pregnancy as long as the CD4 + T lymphocyte could remains above 100-200 cells/ml. For patients requiring therapy, amphotericin B may be preferred, especially during the first trimester. Effective birth control measures should be recommended to all HIV-infected women on azole therapy for cryptococcosis (AIII).

HISTOPLASMOSIS
Prevention of exposure 1. Although HIV-infected persons living in or visiting histoplasmosis-endemic areas cannot completely avoid exposure to Histoplasma capsulatum, those whose CD4 + T lymphocyte counts are less than 200 cells/ml should avoid activities known to be associated with increased risk (e.g., creating dust when working with surface soil; cleaning chicken coops that are heavily contaminated with droppings; disturbing soil beneath bird-roosting sites; cleaning, remodeling or demolishing old buildings; and exploring caves) (CIII).
Prevention of disease 2. Routine skin testing with histoplasmin and serologic testing for antibody or antigen in histoplasmosis-endemic areas are not predictive of disease and should not be performed (DII). 3. Data from a prospective randomized controlled trial indicate that itraconazole can reduce the frequency of histoplasmosis among patients who have advanced HIV infection and who live in H. capsulatumendemic areas 94 . However, no survival benefit was observed among persons receiving itraconazole. Prophylaxis with itraconazole may be considered in patients with CD4 + T lymphocyte counts less than 100 cells/ml who are at especially high risk because of occupational exposure or who live in a community with a hyperendemic rate of histoplasmosis (greater than or equal to ten cases per 100 patient-years) (CI).
Prevention of recurrence 4. Patients who complete initial therapy for histoplasmosis should be administered lifelong suppressive treatment (i.e., secondary prophylaxis or CMT) with itraconazole (200 mg twice a day) (AI) 94 . 5. Although patients receiving secondary prophylaxis (CMT) might be at low risk for recurrence of systemic mycosis when their CD4 + T lymphocyte counts increase to greater than 100 cells/ml, in response to HAART, the numbers of patients who have been evaluated are insufficient to warrant a recommendation to discontinue prophylaxis.

Discontinuation of secondary prophylaxis (CMT)
Special considerations Children 6. Because primary histoplasmosis can lead to disseminated infection in children, a reasonable option is to administer lifelong suppressive therapy after an acute episode of the disease (AIII).

Pregnant women
7. Because of the embryotoxicity and teratogenicity of itraconazole in animal systems, primary prophylaxis against histoplasmosis should not be offered during pregnancy (DIII) 81 . These data as well as the observation of craniofacial and skeletal abnormalities in infants following prolonged in utero exposure to fluconazole 86,87 should be considered when assessing the need for CMT in HIV-infected pregnant women with histoplasmosis. For such patients, therapy with amphotericin B may be preferred, especially during the first trimester. For women receiving HAART with a sustained rise in CD4 + T lymphocyte counts above 100 cells/ml, discontinuation of azole prophylaxis, especially during the first trimester, should be considered. Effective birth control measures should be recommended to all HIV-infected women on azole therapy for histoplasmosis (AIII).

COCCIDIOIDOMYCOSIS
Prevention of exposure 1. Although HIV-infected persons living in or visiting areas in which coccidioidomycosis is endemic cannot completely avoid exposure to Coccidioides immitis, they should, when possible, avoid activities associated with increased risk (e.g., those involving extensive exposure to disturbed native soil, for example, at building excavation sites or during dust storms) (CIII).
Prevention of disease 2. Routine skin testing with coccidioidin (spherulin) in coccidioidomycosis-endemic areas is not predictive of disease and should not be performed (DII). Within the endemic area, a positive serologic test might indicate an increased risk for active infection; however, routine testing does not appear to be useful and should not be performed (DIII). 3. Primary prophylaxis for HIV-infected persons who live in coccidioidomycosis-endemic areas is not routinely recommended.
Prevention of recurrence 4. Patients who complete initial therapy for coccidioidomycosis should be administered lifelong suppressive therapy (i.e., secondary prophylaxis or CMT) (AII) using either 400 mg of fluconazole by mouth each day or 200 mg of itraconazole twice a day 96 . Patients with meningeal disease require consultation with an expert.
Discontinuation of secondary prophylaxis (CMT) 5. Although patients receiving secondary prophylaxis (CMT) might be at low risk for recurrence of systemic mycosis when their CD4 + T lymphocyte counts increase to greater than 100 cells/ml, in response to HAART, the numbers of patients who have been evaluated are insufficient to warrant a recommendation to discontinue prophylaxis.
Special considerations Children 6. Although no specific data are available regarding coccidioidomycosis in HIV-infected children, a reasonable option is to administer lifelong suppressive therapy after an acute episode of the disease (AIII).

Pregnant women
7. The potential teratogenicity of fluconazole 86,87 and itraconazole 81 should be considered when assessing the therapeutic options for HIV-infected women who become pregnant while receiving CMT for coccidioidomycosis. For such patients, therapy with amphotericin B may be preferred, especially during the first trimester. For women receiving HAART with a sustained rise in CD4 + T lymphocyte counts above 100 cells/ml, discontinuation of azole prophylaxis, especially during the first trimester, should be considered. Effective birth control measures should be recommended for all HIV-infected women on azole therapy for coccidioidomycosis (AIII).

CYTOMEGALOVIRUS DISEASE
Prevention of exposure 1. HIV-infected persons who belong to risk groups with relatively low rates of seropositivity for cytomegalovirus (CMV) and who therefore cannot be presumed to be seropositive should be tested for antibody to CMV (BIII). These groups include patients who have not had male homosexual contact or used injection drugs. 2. HIV-infected adolescents and adults should be advised that CMV is shed in semen, cervical secretions and saliva and that latex condoms must always be used during sexual contact to reduce the risk for exposure to CMV and to other sexually transmitted pathogens (AII). 3. HIV-infected adults and adolescents who are child-care providers or parents of children in child-care facilities should be informed that they are at increased risk for acquiring CMV infection (BI). Similarly, parents and other caretakers of HIV-infected children should be advised of the increased risk to children at these centers (BIII). The risk for acquiring CMV infection can be diminished by good hygienic practices such as hand washing (AII). 4. HIV-exposed infants and HIV-infected children, adolescents, and adults who are seronegative for CMV and require blood transfusion should be administered only CMV antibody-negative or leukocyte-reduced cellular blood products in nonemergency situations (BIII).
Prevention of disease 5. Prophylaxis with oral ganciclovir may be considered for HIV-infected adults and adolescents who are CMV seropositive and who have a CD4 + T lymphocyte count of less than 50 cells/ml (CI) 97,98 . Ganciclovir-induced neutropenia, anemia, conflicting reports of efficacy, lack of proven survival benefit, the risk for developing ganciclovir-resistant CMV and cost are among the issues that should be considered when deciding whether to institute prophylaxis in individual patients. Acyclovir is not effective in preventing CMV disease, and valacyclovir is not recommended because of an unexplained trend toward increased deaths among persons with AIDS who were administered valacyclovir for CMV prophylaxis 99 . Therefore, neither acyclovir nor valacyclovir should be used for this purpose (EI). The most important method for preventing severe CMV disease is recognition of the early manifestations of the disease. Early recognition of CMV retinitis is most likely when the patient has been educated on this topic. Patients should be made aware of the significance of increased floaters in the eye and should be advised to assess their visual acuity regularly by using simple techniques such as reading newsprint (BIII). Regular funduscopic examinations performed by an ophthalmologist are recommended by some experts for patients with low (e.g., less than 50 cells/ml) CD4 + T lymphocyte counts (CIII).

Prevention of recurrence
6. CMV disease is not cured with courses of the currently available antiviral agents (e.g., ganciclovir, foscarnet, cidofovir or fomivirsen). Following induction therapy, secondary prophylaxis (CMT) is recommended for life (AI), unless there is immune reconstitution as a consequence of HAART (see recommendation 7 below). Regimens demonstrated to be effective for chronic suppression in randomized, controlled clinical trials include parenteral or oral ganciclovir, parenteral foscarnet, combined parenteral ganciclovir and foscarnet, parenteral cidofovir, and (for retinitis only) ganciclovir administration via intraocular implant or repetitive intravitreous injections of fomivirsen (AI) 100-108 . Oral valganciclovir has been approved by the FDA for both acute induction therapy and for maintenance therapy although much of the data have not been published. Repetitive intravitreous injections of ganciclovir, foscarnet and cidofovir have been reported to be effective for secondary prophylaxis of CMV retinitis in uncontrolled case series 109,110 . Intraocular therapy alone does not provide protection to the contralateral eye or to other organ systems and typically is combined with oral ganciclovir 100 . The choice of a CMT for patients treated for CMV disease should be made in consultation with an expert. For patients with retinitis, this decision should be made in consultation with an ophthalmologist and should take into consideration the anatomic location of the retinal lesion, vision in the contralateral eye, the immunologic and virologic status of the patient, and the patient's response to HAART (BIII).

Discontinuation of secondary prophylaxis (CMT)
7. Several case series have reported that maintenance therapy can be discontinued safely in adult and adolescent patients with CMV retinitis whose CD4 + T lymphocyte counts have shown a sustained (e.g., six months) increase to > 100-150 cells/ml in response to HAART 112-116 . These patients have remained disease-free for greater than 30-95 weeks, whereas in the pre-HAART era, retinitis typically reactivated within 6-8 weeks after stopping CMV therapy. Plasma HIV RNA levels were variable in these patients, suggesting that the CD4 + T lymphocyte count is the primary determinant of immune recovery to CMV. Discontinuation of prophylaxis should be considered in patients with a sustained, (e.g., 6 months) increase in CD4 + T lymphocyte count to > 100-150 cells/ml in response to HAART (BII). Such decisions should be made in consultation with an ophthalmologist and should take into account such factors as magnitude and duration of CD4 + T lymphocyte increase, anatomic location of the retinal lesion, vision in the contralateral eye and the feasibility of regular ophthalmologic monitoring (BII). All patients who have had anti-CMV maintenance therapy discontinued should continue to undergo regular ophthalmologic monitoring for early detection of CMV relapse (as well as for immune reconstitution uveitis) (AIII). CMV viral load or other markers of CMV infection, e.g., antigenemia or viral DNA tests are not well standardized; their role in predicting relapse remains to be defined [117][118] . Relapses have been reported rarely in patients with CD4 + T lymphocyte count > 100-150 cells/ml 119 .
Restarting secondary prophylaxis 8. Relapse of CMV retinitis occurs in patients whose anti-CMV maintenance therapy has been discontinued and whose CD4 + T lymphocyte count has decreased to 50 cells/ml 109 . Therefore, reinstitution of secondary prophylaxis should be reinstituted when the CD4 + T-lymphocyte count has decreased to 100-150 cells/ml (AIII). Relapse has been reported in patients whose CD4 + T lymphocyte counts are higher then 100 cells/ml, but such reports are rare to date 119 .

Special considerations
Children 9. Some experts recommend obtaining a CMV urine culture on all HIV-infected (or exposed) infants at birth or at an early postnatal visit to identify those infants with congenital CMV infection (CIII). In addition, beginning at one year of age, CMV antibody testing on an annual basis may be considered for CMV-seronegative (and culture-negative) HIV-infected infants and children who are severely immunosuppressed (Table 10) (CIII). Annual testing will allow identification of children who have acquired CMV infection and might benefit from screening for retinitis. 10. HIV-infected children who are CMV-infected and severely immunosuppressed might benefit from a dilated retinal examination performed by an ophthalmologist every 4-6 months (CIII). In addition, older children should be counseled to be aware of floaters in the eye, similar to the recommendation for adults (BIII). 11. Oral ganciclovir results in reduced CMV shedding in CMV-infected children and may be considered for primary prophylaxis against CMV disease in CMV-infected children who are severely immunosuppressed (e.g., CD4 + T lymphocyte count less than 50 cells/ml) (CII). 12. Patients with a history of CMV disease should be administered lifelong prophlyaxis to prevent recurrence (AII). For children with CMV disease, no data are available to guide decisions concerning discontinuation of secondary prophylaxis (CMT) when the CD4+ T lymphocyte count has increased in response to HAART. 13. Indications for prophylaxis are the same for pregnant women as for non-pregnant women. The choice of agents to be used in pregnancy should be individualized after consultation with experts.

HERPES SIMPLEX VIRUS DISEASE
Prevention of exposure 1. HIV-infected persons should use latex condoms during every act of sexual intercourse to reduce the risk for exposure to herpes simplex virus (HSV) and to other sexually transmitted pathogens (AII). They should specifically avoid sexual contact when herpetic lesions (genital or orolabial) are evident (AII).
2. Antiviral prophylaxis after exposure to HSV, or to prevent initial episodes of HSV disease in individuals with latent infection is not recommended (DIII).

Prevention of recurrence
3. Because episodes of HSV disease can be treated successfully, chronic therapy with acyclovir is not required after lesions resolve. However, persons who have frequent or severe recurrences can be administered daily suppressive therapy with oral acyclovir or oral famciclovir (AI) [120][121] . Valacyclovir also is an option (CIII). Foscarnet or cidofovir i.v. can be used to treat infection due to acyclovir-resistant isolates of HSV, which are routinely resistant to ganciclovir as well (AII).
Special considerations Children 4. The recommendations for preventing initial disease and recurrence among adults and adolescents apply to children as well.

Pregnant women
5. Oral acyclovir prophylaxis during late pregnancy is a controversial strategy recommended by some experts to prevent neonatal herpes transmission. However, such prophylaxis is not routinely recommended. For patients who have frequent, severe recurrences of genital HSV disease, acyclovir prophylaxis might be indicated (BIII). No pattern of adverse pregnancy outcomes has been reported after acyclovir exposures 122 .

VARICELLA-ZOSTER VIRUS DISEASE
Prevention of exposure 1. HIV-infected children and adults who are susceptible to varicella-zoster virus (VZV) (i.e., those who have no history of chickenpox or shingles or are seronegative for VZV) should avoid exposure to persons with chickenpox or shingles (AII). Household contacts (especially children) of susceptible HIV-infected persons should be vaccinated against VZV if they have no history of chickenpox and are seronegative for HIV, so that they will not transmit VZV to their susceptible HIV-infected contacts (BIII).
Prevention of disease 2. Very little data regarding the safety and efficacy of varicella vaccine in HIV-infected adults are available, and no recommendation for its use can be made for this population. (See Special Considerations/Children, below). 3. For the prophylaxis of chickenpox, HIV-infected children and adults who are susceptible to VZV (i.e., those who have no history of chickenpox or shingles or who have no detectable antibody against VZV) should be administered varicella zoster immune globulin (VZIG) as soon as possible but within 96 h after close contact with a patient who has chickenpox or shingles (AIII). Data are lacking on the effectiveness of acyclovir for preventing chickenpox in susceptible HIV-infected children or adults. 4. No preventive measures are currently available for shingles.
Prevention of recurrence 5. No drug has been proven to prevent the recurrence of shingles in HIV-infected persons.
Special considerations Children 6. HIV-infected children who are asymptomatic and not immunosuppressed (i.e., in immunologic category 1, Table 10) should receive live attenuated varicella vaccine at 12-15 months of age or later (BII). Varicella vaccine should not be administered to other HIV-infected children because of the potential for disseminated viral infection (EIII).

Pregnant women
7. VZIG is recommended for VZV-susceptible, HIV-infected pregnant women within 96 h after exposure to VZV (AIII). If oral acyclovir is used, VZV serology should be performed so that the drug can be discontinued if the patient is seropositive for VZV (BIII).

HUMAN HERPESVIRUS 8 INFECTION (KAPOSI'S SARCOMA-ASSOCIATED HERPES VIRUS)
Prevention of exposure  4. For patients whose Pap smears are interpreted as atypical squamous cells of undetermined significance (ASCUS), several management options are available; the choice depends in part on whether the interpretation of ASCUS is qualified by a statement indicating that a neoplastic process is suspected. Follow-up by Pap tests without colposcopy is acceptable, particularly when the diagnosis of ASCUS is not qualified further or the cytopathologist suspects a reactive process. In such situations, Pap tests should be repeated every 4-6 months for 2 years until three consecutive smears have been negative. If a second report of ASCUS occurs in the 2-year follow-up period, the patient should be considered for colposcopic evaluation (BIII). 5. Women who have a diagnosis of unqualified ASCUS associated with severe inflammation should be evaluated for an infectious process. If specific infections are identified, reevaluation should be performed after appropriate treatment, preferably after 2-3 months (BIII). 6. If the diagnosis of ASCUS is qualified by a statement indicating that a neoplastic process is suspected, the patient should be managed as if a low-grade squamous intraepithelial lesion (LSIL) were present (see recommendation 7) (BIII). If a patient who has a diagnosis of ASCUS is at high risk (i.e., previous positive Pap tests or poor adherence to follow-up), the option of colposcopy should be considered (BIII). 7. Several management options are available for patients who have LSIL. Follow up with Pap tests every 4-6 months is used by many clinicians and is currently used in countries outside the United States as an established method of management. Patients managed in this way must be carefully selected and considered reliable for follow-up. If repeat smears show persistent abnormalities, colposcopy and directed biopsy are indicated (BIII). Colposcopy and directed biopsy of any abnormal area on the ectocervix constitute another appropriate option (BIII). 8. Women who have cytologic diagnosis of high-grade squamous intraepithelial lesions (HSILs) or squamous cell carcinoma should undergo colposcopy and directed biopsy (AII). 9. No data are available to suggest that these guidelines to prevent cervical disease should be modified for women on HAART. HPV-associated anal intraepithelial neoplasia and anal cancer in HIV-infected homosexuals and in women 10. Evidence from several studies shows that HPV-positive homosexuals and HPV infected women are at increased risk for anal HSILs and might be at increased risk for anal cancer. In view of this evidence, coupled with a recent cost-effectiveness analysis projecting that screening and treatment for anal HSILs provide clinical benefits comparable to other measures to prevent OIs in HIV-infected persons 131 , anal cytology screening of HIV-infected homosexuals and women might become a useful preventive measure in the near future. However, further studies of screening and treatment programs for anal HSILs need to be carried out before recommendations for routine anal cytology screening can be made.

Persons co-infected with HIV and HHV-8 are at risk for developing Kaposi's sarcoma (KS) and, there is evidence that progression to KS may be accelerated in individuals who seroconvert to HHV-8 after being infected with HIV. Thus it is important to prevent acquisition of HHV-8 infections in those already infected with HIV 123-125 . The three major routes of HHV-8 transmission appear to be oral (the virus infects oral epithelial cells, and infection has been associated
Prevention of recurrence 11. The risks for recurrence of squamous intraepithelial lesions and cervical cancer after conventional therapy are increased among HIV-infected women. The prevention of illness associated with recurrence depends on careful follow-up of patients after treatment. Patients should be monitored with frequent cytologic screening and, when indicated, with colposcopic examination for recurrent lesions (AI) 134,144 . 12. In one recent study of HIV-infected women treated for HSILs using standard therapy, low-dose intravaginal 5-fluorouracil (2 g twice a week for six months) reduced the short-term risk for recurrence and possibly the grade of recurrence 136 . However, clinical experience with this therapy is too limited to provide a recommendation for routine use.

Special considerations
Pregnant women 13. Use of intravaginal 5-fluorouracil to prevent recurrent dysplasia is not recommended during pregnancy.

HEPATITIS C VIRUS INFECTION
Prevention of exposure 1. The chief route of hepatitis C virus (HCV) transmission in the United States is injection drug use. Because injection drug use is a complex behavior, clinicians should assess the individual's readiness to change this practice and encourage efforts to provide patient education and support directed at recovery.
Patients who inject drugs should be advised [137][138][139] (a) to stop using injection drugs (AIII); (b) to enter and complete a substance-abuse treatment program, including a relapse prevention program (AIII).

If they are continuing to inject drugs (BIII)
to never reuse or share syringes, needles, rinse water or drug preparation equipment; if, nonetheless, injection equipment that has been used by other persons is shared, to first clean the equipment with bleach and water as is recommended for prevention of HIV; to use only sterile syringes obtained from a reliable source (e.g., pharmacies or syringe exchange programs); to use sterile (e.g., boiled) water to prepare drugs; if not possible, to use clean water from a reliable source (e.g., fresh tap water); to use a new or disinfected container (cooker) and a new filter (cotton) to prepare drugs; to clean the injection site with a new alcohol swab before injection; and to safely dispose of syringes after one use. 2. Persons considering tattooing or body piercing should be informed of potential risks of acquiring bloodborne infections, which could be transmitted if equipment is not sterile or if proper infection control procedures are not followed (e.g., washing hands, using latex gloves and cleaning and disinfecting surfaces) 139 (BIII). 3. To reduce risks for acquiring bloodborne infections, patients should be advised not to share dental appliances, razors or other personal care articles (BIII). 4. Although the efficiency of sexual transmission of HCV is low, safe-sexual practices should be encouraged for all HIV infected persons and barrier precautions (e.g., latex condoms) are recommended to reduce the risk for exposure to sexually transmitted pathogens (AII).

All patients with HIV infection should be screened for HCV infection (BIII).
Screening is recommended because some HIV-infected patients (e.g., injection drug users, and patients with hemophilia) are at increased risk for HCV infection and HCV related disease, and because knowledge of HCV status is important for management of all HIV-infected patients (e.g., to interpret and manage elevated liver related tests). Screening should be performed by using enzyme immunoassays (EIAs) licensed for detection of antibody to HCV (anti-HCV) in blood (BIII). Positive anti-HCV results should be verified with additional testing (i.e., recombinant immunoblot assay [RIBAÔ] or reverse transcriptase polymerase chain reaction (RT-PCR) for HCV RNA). The presence of HCV RNA in blood might also be assessed in HIV-infected persons with undetectable antibody but other evidence of chronic liver disease (e.g., unexplained elevated liver-specific enzymes) or when acute HCV infection is suspected (CIII). 6. Persons coinfected with HIV and HCV should be advised not to drink excessive amounts of alcohol (AII). Avoiding alcohol altogether might be prudent because it is unclear whether even occasional alcohol use (e.g., less than 12 ounces of beer or less than 10 grams of alcohol per day) increases the incidence of cirrhosis among HCV-infected persons (CIII). 7. Patients with chronic hepatitis C should be vaccinated against hepatitis A because a) the risk for fulminant hepatitis associated with hepatitis A appears increased in such patients; b) hepatitis A vaccine is safe for HIV-infected persons; and c) although immunogenicity is reduced in patients with advanced HIV infection, more than two thirds of patients develop protective antibody responses (BIII). Prevaccination screening for total (IgG and IgM) antibody to hepatitis A virus is cost-effective and therefore recommended when greater than 30% prevalence of hepatitis A virus antibody is expected in the population being screened (e.g., persons greater than 40 years of age) 140 . Patients should also be immunized for HBV if they are susceptible (BIII). 8. HIV-HCV-coinfected patients may develop HCV associated liver disease over a shorter time course than patients infected with HCV alone [141][142][143][144] and should be evaluated for chronic liver disease and for the possible need for treatment. Limited data suggest that HCV treatment can be safely provided to patients coinfected with HIV and HCV. Because the optimal means of treating coinfected patients has not been established and many HIV-infected patients have conditions that complicate therapy (e.g., depression), this care should occur in a clinical trial or be coordinated by providers with experience treating both HIV and HCV infections (BIII). 9. In some studies, the incidence of antiretroviral-associated liver enzyme elevations has been increased in patients coinfected with HIV and HCV 142 ; such increases might not require treatment modifications. Thus, although liver enzymes should be carefully monitored, HAART should not be routinely withheld from patients coinfected with HIV and HCV (DIII). However, coinfected patients initiating HAART might have an inflammatory reaction that mimics an exacerbation of underlying liver disease. In this situation, careful monitoring of liver function is required.

Prevention of recurrence
10. If the serum HCV RNA level becomes undetectable during HCV therapy and remains undetectable for 6 months after HCV therapy is stopped (sustained virologic response), greater than 90% of HIVuninfected patients with hepatitis C will remain HCV RNA negative for greater than five years and have improved liver histology 145 . For HIV-HCV-coinfected patients, the durability of treatment response and requirement for maintenance therapy are unknown.

Special considerations
Children 11. Transmission of HCV from mother to child appears to be more frequent for mothers co-infected with HIV and HCV than for those infected with HCV alone. Therefore, children born to women coinfected with HIV and HCV should be tested for HCV infection 137 (BI). Because maternal HCV antibody can persist for up to 18 months, testing should be performed at or after two years of age. If earlier diagnosis is desired, RT-PCR for HCV RNA may be performed after one month of age and should be repeated at a subsequent time. The average rate of HCV infection among infants born to coinfected women is approximately 15% (range, 5-36%) 146 . Data are limited on the natural history of HCV infection and treatment of chronic hepatitis C in children. In addition, anmtiviral treatment for chronic hepatitis C is not approved for patients < 18 years of age.

Hepatitis A immunization is recommended for all susceptible men who have sex with men, as well as others with indications for HAV vaccine (BIII).
persons boil or otherwise avoid drinking tap water in nonoutbreak settings. However, persons who wish to take independent action to reduce their risk for waterborne cryptosporidiosis may choose to take precautions similar to those recommended during outbreaks. Such decisions are best made in conjunction with a health-care provider. Persons who opt for a personal-use filter or bottled water should be aware of the complexities involved in selecting the appropriate products, the lack of enforceable standards for destruction or removal of oocysts, the cost of the products, and the difficulty of using these products consistently. Patients taking 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 should be aware that fountain beverages served in restaurants, bars, theaters, and other public places might also pose a risk, because these bever-ages, as well as the ice they might 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 juices labeled as pasteurized should be considered free of risk from Cryptosporidium. Other pasteurized beverages and beers are also considered safe to drink (BII). No data are available concerning survival of Cryptosporidium oocystsin wine.