Guidelines for Preventing Opportunistic Infections among HIV-Infected Persons—2002: Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America* FREE

In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) among persons infected with human immunodeficiency virus (HIV) (1–3). These guidelines, which are intended for clinicians and health-care providers and their HIV-infected patients, were revised in 1997 (4) and again in 1999 (5), and have been published in MMWR(1, 4–5), Clinical Infectious Diseases(2, 6–7), Annals of Internal Medicine(3, 8), American Family Physician(9–10), and Pediatrics(11); accompanying editorials have appeared in JAMA(12–13). Response to these guidelines (e.g., a substantial number of requests for reprints, website contacts, and observations from health-care providers) demonstrates that they have served as a valuable reference for HIV health-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 acquired immunodeficiency syndrome (AIDS) was first recognized 20 years ago, remarkable progress has been made in improving the quality and duration of life for HIV-infected persons in the industrialized world. During the first decade of the epidemic, this improvement occurred because of improved recognition of opportunistic disease processes, improved therapy for acute and chronic complications, and introduction of chemoprophylaxis against key 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 OIs. HAART has reduced the incidence of OIs and extended life substantially (14–16). HAART is the most effective approach to preventing OIs and should be considered for all HIV-infected persons who qualify for such therapy (14–16). However, certain patients are not ready or able to take HAART, and others have tried HAART regimens but therapy 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).

Clearly, since HAART was introduced in the United States in 1995, chemoprophylaxis for OIs need not be lifelong. Antiretroviral therapy can restore immune function. The period of susceptibility to opportunistic processes continues to be accurately indicated by CD4⁺ T lymphocyte counts 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 is logical. Stopping prophylactic regimens can simplify treatment, reduce toxicity and drug interactions, lower cost of care, and potentially facilitate adherence to antiretroviral regimens.

In 1999, the USPHS/IDSA guidelines reported that stopping primary or secondary prophylaxis for certain pathogens was safe 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 regarding discontinuing 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, certain inconsistencies in the format of these criteria are 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 OIs. For primary prophylaxis, whether to use the same threshold at which prophylaxis can 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 certain cases, ranges are provided for restarting primary or secondary prophylaxis. For prophylaxis against Pneumocystis carinii pneumonia (PCP), the indicated threshold for restarting both primary and secondary prophylaxis is 200 cells/µL. For all these recommendations, the Roman numeral ratings reflect the lack of data available to assist in making these decisions (Box).

During the development of these revised guidelines, working group members reviewed published manuscripts as well as abstracts and material presented at professional meetings. Periodic teleconferences were held to develop the revisions.

Major changes in the guidelines since 1999 include the following:

For each of the 19 diseases covered in this report, specific recommendations are provided that address 1) preventing exposure to opportunistic pathogens, 2) preventing first episodes of disease, and 3) preventing disease recurrences. 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 (Box).

Because of their length and complexity, tables in this report are grouped together and follow the references. Tables appear in the following order:

Table 1 Dosages for prophylaxis to prevent first episode of opportunistic disease among infected adults and adolescents;

Table 2 Dosages for prophylaxis to prevent recurrence of opportunistic disease among 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 prevent OIs;

Table 7 Dosages of drugs for preventing OIs for persons with renal insufficiency;

Table 8 Costs of agents recommended for preventing OIs among adults with HIV infection;

Table 9 Immunologic categories for HIV-infected children;

Table 10 Immunization schedule for HIV-infected children;

Table 11 Dosages for prophylaxis to prevent first episode of opportunistic disease among HIV-infected infants and children;

Table 12 Dosages for prophylaxis to prevent recurrence of opportunistic disease among HIV-infected infants and children; and

Table 13 Criteria for discontinuing and restarting OI prophylaxis for adult patients with HIV infection.

Recommendations advising patients how to prevent exposure to opportunistic pathogens are also included in this report (Appendix).

This report is oriented toward preventing specific OIs among HIV-infected persons in the United States and other industrialized countries. Recommendations for using HAART, which is designed to prevent immunologic deterioration, restore immune function, and delay the need for certain chemoprophylactic strategies described in this report, were originally published elsewhere (14) and are updated regularly (available at http://www.hivatis.org) (16).

Pamphlets related to preventing OIs can be obtained from the HIV/AIDS Treatment Information Service (ATIS) by calling 800-448-0440, 301-519-0459 (international), or 888-480-3739 (TTY). They also can be accessed on the CDC and ATIS websites at http://www.cdc.gov/hiv/pubs/brochure.htm and http://www.hivatis.org, respectively.

New data regarding preventing OIs among HIV-infected persons are emerging, and randomized controlled trials addressing unresolved concerns related to OI prophylaxis are ongoing. The OI Working Group reviews emerging data routinely and updates the guidelines regularly.

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

Initiating Primary Prophylaxis. HIV-infected adults and adolescents, including pregnant women and those on HAART, should receive chemoprophylaxis against PCP if they have a CD4⁺ T lymphocyte count of <200/µL (AI) or a history of oropharyngeal candidiasis (AII) (18–20). Persons who have a CD4⁺ T lymphocyte percentage of <14% or a history of an AIDS-defining illness, but do not otherwise qualify, should be considered for prophylaxis (BII) (18–20). When monitoring CD4⁺ T lymphocyte counts for ≥ 3 months is not possible, initiating chemoprophylaxis at a CD4⁺ T lymphocyte count of >200, but <250 cells/µL, also should be considered (BII) (19).

Trimethoprim-sulfamethoxazole (TMP-SMZ) is the recommended prophylactic agent (AI) (20–23). One double-strength tablet daily is the preferred regimen (AI) (23). However, one single-strength tablet daily (23) is also effective and might be better tolerated than one double-strength tablet daily (AI). One double-strength tablet three times weekly is also effective (BI) (24). TMP-SMZ at a dose of one double-strength tablet daily confers cross-protection against toxoplasmosis (25) and selected 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 if clinically feasible; for those who have discontinued such therapy because of an adverse reaction, reinstituting TMP-SMZ should be strongly considered after the adverse event has resolved (AII). Patients who have experienced adverse events, including fever and rash, might better tolerate reintroduction of the drug with a gradual increase in dose (i.e., desensitization), according to published regimens (BI) (27–28) or reintroduction of TMP-SMZ at a reduced dose or frequency (CIII); ≤ 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™ nebulizer (manufactured by Marquest, Englewood, Colorado) (BI), 22) and atovaquone (BI) (31–32). Apparently, atovaquone is 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 cannot be recommended as alternatives because data regarding their efficacy for PCP prophylaxis are insufficient to do so:

However, clinicians might consider using these agents in unusual situations in which the recommended agents cannot be administered (CIII).

Discontinuing Primary Prophylaxis. Primary pneumocystis prophylaxis should be discontinued for adult and adolescent patients who have responded to HAART with an increase in CD4⁺ T lymphocyte counts to >200 cells/µL for ≥ 3 months (AI). In observational and randomized studies supporting this recommendation, the majority of patients were taking antiretroviral regimens that included a protease inhibitor (PI), and the majority had a CD4⁺ T lymphocyte cell count of >200 cells/µL for ≥ 3 months before discontinuing PCP prophylaxis (33–41). The median CD4⁺ T lymphocyte count at the time prophylaxis was discontinued was >300 cells/µL, and certain patients had a sustained suppression of HIV plasma ribonucleic acid (RNA) levels below detection limits of the assay employed. Median follow-up ranged from 6 to 16 months.

Discontinuing primary prophylaxis among these patients is recommended because, apparently, prophylaxis adds limited disease prevention (i.e., for PCP, toxoplasmosis, or bacterial infections) and because discontinuing drugs reduces pill burden, 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/µL (AIII).

Patients who have a history of PCP should be administered chemoprophylaxis for life (i.e., secondary prophylaxis or chronic maintenance therapy) with the regimens listed (Table 2) (AI), unless immune reconstitution occurs as a consequence of HAART (see the following recommendation).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy). Secondary prophylaxis should be discontinued for adult and adolescent patients whose CD4⁺ T lymphocyte cell count has increased from <200 cells/µL to >200 cells/µL for ≥ 3 months as a result of 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 counts to >200 cells/µL for ≥ 3 months. The majority of patients were taking PI-containing regimens. The median CD4⁺ T lymphocyte count at the time prophylaxis was discontinued was >300 cells/µL. The majority of patients had sustained suppression of 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 of >200 cells/µL, continuing PCP prophylaxis for life, regardless of how high the CD4⁺ T lymphocyte count rises as a consequence of HAART, is probably prudent (CIII).

Discontinuing secondary prophylaxis for patients is recommended because, apparently, prophylaxis adds limited disease prevention (i.e., for PCP, toxoplasmosis, or bacterial infections) and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interactions, selection of drug-resistant pathogens, and cost.

Restarting Secondary Prophylaxis. Prophylaxis should be reintroduced if the CD4⁺ T lymphocyte count decreases to <200 cells/µL (AIII) or if PCP recurred at a CD4⁺ T lymphocyte count of >200 cells/µL (CIII).

Children. Children born to HIV-infected mothers should be administered prophylaxis with TMP-SMZ beginning at age 4–6 weeks (44) (AII). Prophylaxis should be discontinued for children who are subsequently determined 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. Need for subsequent prophylaxis should be determined on the basis of age-specific CD4⁺ T lymphocyte count thresholds (Table 11) (AII). The safety of discontinuing prophylaxis among 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). The safety of discontinuing secondary prophylaxis among HIV-infected children has not been studied extensively.

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, health-care providers might choose to withhold prophylaxis during the first trimester. In such cases, aerosolized pentamidine can be considered because of its lack of systemic absorption and the resultant lack of exposure of the developing embryo to the drug (CIII).

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).

All HIV-infected persons, including those who lack IgG antibody to Toxoplasma, should be counseled regarding sources of toxoplasmic infection. They should be advised not to eat raw or undercooked meat, including undercooked lamb, beef, pork, or venison (BIII). Specifically, lamb, beef, and pork should be cooked to an internal temperature of 165 °F–170 °F (44–45); meat cooked until it is no longer pink inside usually has an internal temperature of 165 °F–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, patients should wash their 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).

Initiating Primary Prophylaxis. Toxoplasma-seropositive patients who have a CD4⁺ T lymphocyte count of <100/µL should be administered prophylaxis against toxoplasmic encephalitis (TE) (AII) (25). Apparently, the double-strength tablet daily dose of TMP-SMZ recommended as the preferred regimen for PCP prophylaxis is 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 can be considered (CIII). Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, or clarithromycin cannot be recommended on the basis of available 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 counts decline to <100/µL to determine whether they have seroconverted and are therefore at risk for TE (CIII). Patients who have seroconverted should be administered prophylaxis for TE as described previously (AII).

Discontinuing Primary Prophylaxis. Prophylaxis against TE should be discontinued among adult and adolescent patients who have responded to HAART with an increase in CD4⁺ T lymphocyte counts to >200 cells/L for ≥ 3 months (AI). Multiple observational studies (37, 41, 46) and two randomized trials (38, 48) have reported that primary prophylaxis can be discontinued with minimal risk for experiencing TE among patients who have responded to HAART with an increase in CD4⁺ T lymphocyte count from <200 cells/µL to >200 cells/µL for ≥ 3 months. In these studies, the majority of patients were taking PI-containing regimens and the median CD4⁺ T lymphocyte count at the time prophylaxis was discontinued was >300 cells/µL. At the time prophylaxis was discontinued, certain patients had sustained suppression of plasma HIV RNA levels below the detection limits of available assays; the median follow-up ranged from 7 to 22 months. Although patients with CD4⁺ T lymphocyte counts of <100 cells/µL are at greatest risk for experiencing TE, the risk for TE occurring when the CD4⁺ T lymphocyte count has increased to 100–200 cells/µL has not been studied as rigorously as an increase to >200 cells/µL. Thus, the recommendation specifies discontinuing prophylaxis after an increase to >200 cells/µL. Discontinuing primary TE prophylaxis is recommended because prophylaxis apparently adds limited disease prevention for toxoplasmosis and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interaction, selection of drug-resistant pathogens, and cost.

Restarting Primary Prophylaxis. Prophylaxis should be reintroduced if the CD4⁺ T lymphocyte count decreases to <100–200 cells/µL (AIII).

Patients who have completed initial therapy for TE should be administered lifelong suppressive therapy (i.e., secondary prophylaxis or chronic maintenance therapy) (AI) (49–50) unless immune reconstitution occurs as a consequence of HAART (see the following recommendation). 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, apparently, only the combination of pyrimethamine plus sulfadiazine provides protection against PCP as well (AII).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy). Adult and adolescent patients receiving secondary prophylaxis (i.e., chronic maintenance therapy) for TE are, apparently, at low risk for recurrence of TE when they have successfully completed initial therapy for TE, remain asymptomatic with regard to signs and symptoms of TE, and have a sustained increase in their CD4⁺ T lymphocyte counts of >200 cells/µL after HAART (e.g., ≥ 6 months) (41–42, 47–48). Although the numbers of patients who have been evaluated remain limited and occasional recurrences have been reported, on the basis of these observations and inference from more extensive cumulative data indicating the safety of discontinuing secondary prophylaxis for other OIs during advanced HIV disease, discontinuing chronic maintenance therapy among such patients is a reasonable consideration (CIII). Certain specialists would obtain a magnetic resonance image of the brain as part of their evaluation to determine whether discontinuing therapy is appropriate.

Restarting Secondary Prophylaxis. Secondary prophylaxis (chronic maintenance therapy) should be reintroduced if the CD4⁺ T lymphocyte count decreases to <200 cells/µL (AIII).

Children. TMP-SMZ, when administered for PCP prophylaxis, also provides prophylaxis against toxoplasmosis. Atovaquone might also provide protection (CIII). Children aged >12 months who qualify for PCP prophylaxis and who are receiving an agent other than TMP-SMZ or atovaquone should have serologic testing for Toxoplasma antibody (BIII) because alternative drugs for PCP prophylaxis might not be effective against Toxoplasma. Severely immunosuppressed children who are not receiving TMP-SMZ or atovaquone who are determined 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 among 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, health-care providers and clinicians should be well-informed regarding benefits of lifelong therapy and concerns related to teratogenicity of pyrimethamine. Guidelines provided previously should be used when making decisions regarding secondary prophylaxis for TE during 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).

HIV-infected persons should be educated and counseled concerning the different 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.

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).

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

HIV-infected persons should not drink water directly from lakes or rivers (AIII). Waterborne infection also might result from swallowing water during recreational activities. HIV-infected persons should be aware that lakes, rivers, and saltwater beaches and certain 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).

Outbreaks of cryptosporidiosis have been linked to municipal water supplies. During outbreaks or in other situations in which a community advisory to boil water is issued, boiling water for 1 minute will eliminate the risk for cryptosporidiosis (AI). Using submicron personal-use water filters† (home/office types) or bottled water§ also might reduce the risk (CIII). The magnitude of the risk for acquiring cryptosporidiosis from drinking water in a nonoutbreak setting is uncertain, and available 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 might 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, costs of the products, and the logistic difficulty of using these products consistently.

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

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

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, certain specialists recommend that HIV-infected persons, specifically those who are severely immunocompromised, should not share a room with a patient with cryptosporidiosis (CIII).

Rifabutin or clarithromycin, when taken for MAC prophylaxis, has been found to protect against cryptosporidiosis (51–52). However, data are insufficient to warrant a recommendation for using these drugs as chemoprophylaxis for cryptosporidiosis.

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

Children. No data indicate that formula-preparation practices for infants should be altered to prevent cryptosporidiosis (CIII). However, in the event of a boil-water advisory, similar precautions for preparing infant formula should be taken as for drinking water for adults (AII).

Other than general attention to hand-washing and other personal hygiene measures, no precautions to reduce exposure can be recommended.

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

No chemotherapeutic regimens are known to be effective in preventing recurrence of microsporidiosis.

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

When HIV infection is first recognized, the patient should receive a tuberculin skin test (TST) by administration of intermediate-strength (5-TU) purified protein derivative (PPD) by the Mantoux method (AI). Routine evaluation for anergy is not recommended. However, situations exist in which anergy evaluation might assist in guiding decisions concerning preventive therapy (53–54).

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

All HIV-infected persons, regardless of age, who have a positive TST result but have no evidence of active TB and no history of treatment for active or latent TB should be treated for latent TB infection. Options include isoniazid daily (AII) or twice weekly (BII) for 9 months; 4 months of therapy daily with either rifampin (BIII) or rifabutin (CIII); or 2 months of therapy with either rifampin and pyrazinamide (BI) or rifabutin and pyrazinamide (CIII) (53–55). Reports exist of fatal and severe liver injury associated with treatment of latent TB infection among HIV-uninfected persons treated with the 2-month regimen of daily rifampin and pyrazinamide; therefore, using regimens that do not contain pyrazinamide among HIV-infected persons whose completion of treatment can be ensured is prudent (56). Because HIV-infected persons are at risk for peripheral neuropathy, those receiving isoniazid should also receive pyridoxine (BIII). Decisions to use a regimen containing either rifampin or rifabutin should be made after carefully considering potential drug interactions, including those related to PIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs) (see the following section on Drug Interactions). Directly observed therapy should be used with intermittent dosing regimens (AI) and when otherwise operationally feasible (BIII) (54).

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 a diagnosis of active TB has been excluded (AII) (53–55). In addition to household contacts, such persons might also include contacts in the same drug-treatment or health-care facility, coworkers, and other contacts if transmission of TB is demonstrated.

For persons exposed to isoniazid- or rifampin-resistant TB, decisions 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). TST-negative, HIV-infected persons from groups at risk or geographic areas with a high prevalence of M. tuberculosis infection might be at increased risk for primary or reactivation TB. However, efficacy of treatment among this group has not been demonstrated. Decisions concerning using chemoprophylaxis in these situations must be considered individually.

Although the reliability of 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 a substantial risk for exposure to M. tuberculosis exists (BIII). Clinicians should consider repeating 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 >200 cells/µL) (BIII) (53). 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. Administering bacille Calmette-Guérin (BCG) vaccine to HIV-infected persons is contraindicated because of its potential to cause disseminated disease (EII).

Chronic suppressive therapy for a patient who has successfully completed a recommended regimen of treatment for TB is unnecessary (DII).

Drug Interactions. Rifampin can induce metabolism of all PIs and NNRTIs. This can result in more rapid drug clearance and possibly subtherapeutic drug concentrations of the majority of these antiretroviral agents. Rifampin should not be coadministered with the following PIs and NNRTIs: amprenavir, indinavir, lopinavir/ritonavir, nelfinavir, saquinavir, and delavirdine (55). However, it can 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 PI hard-gel saquinavir or delavirdine; caution is advised if the drug is coadministered with soft-gel saquinavir because data are limited. Rifabutin can be administered at one half the usual daily dose (i.e., reduce from 300 mg to 150 mg/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 a single PI, the dose of indinavir should be increased from 800 mg/8 hours to 1000 mg/8 hours. Pharmacokinetic data indicate that rifabutin at an increased dose can be administered with efavirenz; doses of 450–600 mg/day have been recommended (55). However, available information is limited concerning appropriate dosing if a PI 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. Infants born to HIV-infected mothers should have a TST (5-TU PPD) at or before age 9–12 months, and the infants should be retested ≥ 1 times/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. 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 or pelvic lead apron shields should be used to minimize radiation exposure to the embryo or 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, health-care providers might 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 information with rifampin has not been associated with adverse pregnancy outcomes. Pyrazinamide should usually be avoided, chiefly in the first trimester, because of lack of information concerning fetal effects.

Organisms of MAC are common in environmental sources (e.g., food and water). Available information does not support specific recommendations regarding exposure avoidance.

Initiating Primary Prophylaxis. Adults and adolescents who have HIV infection should receive chemoprophylaxis against disseminated MAC disease if they have a CD4⁺ T lymphocyte count of <50 cells/µL (AI) (57). Clarithromycin (58–59) or azithromycin (60) is the preferred prophylactic agent (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) (60). 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) (60). 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) (55). Tolerance, cost, and drug interactions are among the concerns that should be considered in decisions regarding the choice of prophylactic agents for MAC disease. Particular attention to interactions with antiretroviral PIs and NNRTIs is warranted (see the following section on 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 rifampin resistance among persons who have active TB, active TB should also be excluded before rifabutin is used for prophylaxis.

Although detecting MAC organisms in the respiratory or gastrointestinal tract might predict disseminated MAC infection, no data are available regarding efficacy of prophylaxis with clarithromycin, azithromycin, rifabutin, or other drugs among 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).

Discontinuing Primary Prophylaxis. Primary MAC prophylaxis should be discontinued among adult and adolescent patients who have responded to HAART with an increase in CD4⁺ T lymphocyte counts to >100 cells/µL for ≥ 3 months (AI). Two substantial randomized, placebo controlled trials and observational data have demonstrated that such patients can discontinue primary prophylaxis with minimal risk for experiencing MAC (37, 61–63). Discontinuing primary prophylaxis among patients meeting these criteria is recommended because, apparently, prophylaxis adds limited disease prevention for MAC or for bacterial infections and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interactions, selection of drug-resistant pathogens, and cost.

Restarting Primary Prophylaxis. Primary prophylaxis should be reintroduced if the CD4⁺ T lymphocyte count decreases to <50–100 cells/µL (AIII).

Adult and adolescent patients with disseminated MAC should receive lifelong therapy (i.e., secondary prophylaxis or maintenance therapy) (AII), unless immune reconstitution occurs as a consequence of HAART (see the following recommendation). Unless substantial clinical or laboratory evidence of macrolide resistance exists, using a macrolide (i.e., clarithromycin or, alternatively, azithromycin) is recommended in combination with ethambutol (AII) with or without rifabutin (CI) (64–65). Treatment of MAC disease with clarithromycin in a dose of 1000 mg twice/day is associated with a higher mortality rate than has been observed with clarithromycin administered at 500 mg twice/day; thus, the higher dose should not be used (EI) (66–67). Clofazimine has been associated with adverse clinical outcomes in the treatment of MAC disease and should not be used (DII) (68).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy). Apparently, patients are at low risk for recurrence of MAC when they have completed a course of ≥ 12 months of treatment for MAC, remain asymptomatic with respect to MAC signs and symptoms, and have a sustained increase (e.g., ≥ 6 months), in their CD4⁺ T lymphocyte counts to >100 cells/µL after HAART. Although the numbers of patients who have been evaluated remain limited and recurrences could occur (41–42, 47, 69–71), on the basis of these observations and on inference from more extensive data indicating the safety of discontinuing secondary prophylaxis for other OIs during advanced HIV disease, discontinuing chronic maintenance therapy among such patients is reasonable (CIII). Certain specialists recommend obtaining a blood culture for MAC, even for asymptomatic patients, before discontinuing therapy to substantiate that disease is no longer active.

Restarting Secondary Prophylaxis. Secondary prophylaxis should be reintroduced if the CD4⁺ T lymphocyte count decreases to <100 cells/µL (AIII).

Drug Interactions. Rifabutin should not be administered to patients receiving certain PIs and NNRTIs because the complex interactions have been incompletely studied, and the clinical implications of those interactions are unclear (16, 55) (see Drug Interactions in the Tuberculosis section). PIs can increase clarithromycin levels, but no recommendation to adjust the dose of either clarithromycin or PIs can be made on the basis of existing data. Efavirenz can induce metabolism of clarithromycin. This can 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 unknown, the efficacy of clarithromycin in MAC prophylaxis could be reduced because of this interaction. Azithromycin pharmacokinetics are not affected by the cytochrome P450 (CYP450) system; azithromycin can be used safely in the presence of PIs or NNRTIs without concerns of drug interactions.

Children. HIV-infected children aged <13 years who have advanced immunosuppression also can experience disseminated MAC infections, and prophylaxis should be offered to children at high risk according to the following CD4⁺ T lymphocyte thresholds:

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 among children whose CD4⁺ T lymphocyte counts have increased in response to HAART has not been studied.

Pregnant Women. Chemoprophylaxis for MAC disease should be administered to pregnant women as is done for other adults and adolescents (AIII). However, because of concerns related to administering drugs during the first trimester of pregnancy, certain health-care providers might choose to withhold prophylaxis during the first trimester. Animal studies and anecdotal evidence of safety among humans indicate that, of the available agents, azithromycin is the drug of choice (BIII) (72). Experience with rifabutin is limited. Clarithromycin has been demonstrated to be a teratogen among animals and should be used with caution during pregnancy (73). For secondary prophylaxis (chronic maintenance therapy), azithromycin plus ethambutol are the preferred drugs (BIII) (72).

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 ≥ 200 cells/µL should be administered a single dose of 23-valent polysaccharide pneumococcal vaccine (PPV) if they have not received this vaccine during the previous five years (BII) (74–78). One randomized placebo-controlled trial of pneumococcal vaccine in Africa paradoxically determined that an increase had occurred in pneumonia among vaccinated subjects (79). However, multiple observational studies in the United States have not identified increased risk associated with vaccination and have identified benefit among this group (74–78). The majority of HIV specialists 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 of <200 cells/µL, although clinical evidence has not confirmed efficacy (CIII). Revaccination can be considered for patients who were initially immunized when their CD4⁺ T lymphocyte counts were <200 cells/µL and whose CD4⁺ counts have increased to >200 cells/µL 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 β-lactam–resistant) strains of S. pneumoniae.

The duration of the protective effect of primary pneumococcal vaccination is unknown. Periodic revaccination can be considered; an interval of 5 years has been recommended for persons not infected with HIV and also might be appropriate for persons infected with HIV (CIII) (77). However, no evidence confirms clinical benefit from revaccination.

Incidence of H. influenzae type B (Hib) infection among adults is low. Therefore, Hib vaccine is not usually recommended for adult use (DIII). TMP-SMZ, when administered daily for PCP prophylaxis, reduces the frequency of bacterial respiratory infections. This should be considered in selecting an agent for PCP prophylaxis (AII). However, indiscriminate use of this drug (when not indicated for PCP prophylaxis or other specific reasons) might promote 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 selecting an agent for prophylaxis against MAC disease (BII). However, these drugs should not be prescribed solely for preventing bacterial respiratory infection (DIII).

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, health-care providers might consider taking steps to reverse neutropenia, either by stopping myelosuppressive drugs (CII) or by administering granulocyte-colony-stimulating factor (G-CSF) (CII).

Clinicians can administer antibiotic chemoprophylaxis to HIV-infected patients who have 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, health-care providers should be cautious when using antibiotics solely for preventing the recurrence of serious bacterial respiratory infections because of the potential development of drug-resistant microorganisms and drug toxicity.

Children. HIV-infected children aged <5 years should be administered Hib vaccine (AII) and pneumococcal conjugate vaccine (PCV) (80–82) (BII) in accordance with the guidelines of the Advisory Committee on Immunization Practices (75, 77, 80) and the American Academy of Pediatrics (81). Children aged >2 years should also receive 23-valent PPV (BII). Revaccination with a second dose of the 23-valent PPV should usually be administered after 3–5 years to children aged ≤ 10 years and after 5 years to children aged >10 years (BIII).

To prevent serious bacterial infections among HIV-infected children who have hypogammaglobulinemia (IgG <400 mg/dL), clinicians should use intravenous immune globulin (IVIG) (AI). Respiratory syncytial virus (RSV) IVIG (750 mg/kg body weight), not monoclonal RSV antibody, can be substituted for IVIG during the RSV season to provide broad anti-infective protection, if RSV IVIG is available.

To prevent recurrence of serious bacterial respiratory infections, antibiotic chemoprophylaxis can be considered (BI). However, health-care providers should be cautious when using antibiotics solely for this purpose because of the potential development of drug-resistant microorganisms and drug toxicity. Administering IVIG should also be considered for HIV-infected children who have recurrent serious bacterial infections (BI), although such treatment might not provide additional benefit to children who are being administered daily TMP-SMZ. However, IVIG can be considered for children who have recurrent serious bacterial infections despite receiving TMP-SMZ or other antimicrobials (CIII) (83).

Pregnant Women. Pneumococcal vaccination is recommended during pregnancy for HIV-infected patients who have not been vaccinated during the previous 5 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 can be deferred until after HAART has been initiated to prevent perinatal HIV transmission (CIII).