1999 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with HIV: Part II. Prevention of the First Episode of Disease - January 15, 2000

1999 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with HIV: Part II. Prevention of the First Episode of Disease

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, PUBLIC HEALTH SERVICE CENTERS FOR DISEASE CONTROL AND PREVENTION

Atlanta, Georgia

This second part of the adapted "Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus" gives recommendations for the prevention of the first episode of certain diseases that may occur in patients with human immunodeficiency virus (HIV) infection. Table 1¹(page 442) gives a description of the rating system used by the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) to rate recommendations. In this system, a letter rating (letters A through E) signifies the strength of the recommendation, and a Roman numeral (numerals I through III) indicates the quality of the evidence supporting that recommendation.

TABLE 1
Rating System for Strength of Recommendation and Quality of Evidence Supporting the Recommendation

Rating
Definition

Ratings reflecting the strength of each recommendation

A Strong evidence for efficacy and substantial clinical benefit support recommendation for use. Should always be offered.

B Moderate evidence for efficacy--or strong evidence for efficacy but only limited clinical benefit--supports recommendation for use. Should generally be offered.

C 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.

D Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should generally not be offered.

E Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should never be offered.

Ratings reflecting the quality of evidence supporting each recommendation

I Evidence from at least one properly randomized, controlled trial.

II 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.

III Evidence from opinions of respected authorities based on clinical experience, descriptive studies or reports of expert committees.

Adapted with permission from Gross PA, Barrett TL, Dellinger EP, Krause PJ, Martone WI, McGowan JE, et al. Purpose of quality standards for infectious diseases. Infectious Diseases Society of America. Clin Infect Dis 1994;18:421.

Dosages for prophylaxis to prevent a first episode of opportunistic disease in HIV-infected adults and adolescents are given in Table 2 (page 446); effects of food on drugs used to treat opportunistic infections are given in Table 3 (page 448); effects of medications on drugs used to treat opportunistic infections are given in Table 4 (page 449); effects of opportunistic infection medications on drugs commonly administered to HIV-infected persons are given in Table 5 (page 453); adverse effects of drugs used to manage HIV infection are given in Table 6 (page 456); dosages of drugs for prevention of opportunistic infections in persons with renal insufficiency are given in Table 7 (page 457); costs of agents recommended for the prevention of opportunistic infections in adults with HIV infection are given in Table 8 (page 458); and criteria for discontinuing and restarting opportunistic infection prophylaxis in adult patients with HIV infection are given in Table 9 (page 461). Table 10 (page 465) gives the immunologic categories for children with HIV, and Table 11 (page 466) summarizes prophylaxis for prevention of first episodes of opportunistic disease in infants and children with HIV. Figure 1 (page 468) gives the recommended immunization schedule for HIV-infected infants and children.

This report is oriented toward the prevention of specific opportunistic infections in HIV-infected persons in the United States and other industrialized countries. Recommendations for use of antiretroviral therapy, which is designed to prevent immunologic deterioration and delay the need for many of the chemoprophylactic strategies described in this report, are published elsewhere,² as are integrated approaches to the care of HIV-infected persons.³

Disease-Specific Recommendations for the Prevention of the First Episode

Pneumocystis carinii Pneumonia
Initiation of Primary Prophylaxis. Adults and adolescents who have HIV infection, including pregnant women and those receiving highly active antiretroviral therapies (HAART), should receive chemoprophylaxis against Pneumocystis carinii pneumonia (PCP) if they have a CD4+ T-lymphocyte count of less than 200 per mm³ (200 x 10⁶ per L) (AI) or a history of oropharyngeal candidiasis (AII).⁴ Persons who have a CD4+ T-lymphocyte percentage of less than 14 percent or a history of an acquired immunodeficiency syndrome (AIDS)-defining illness but do not otherwise qualify should be considered for prophylaxis (BII).^5,6 When monitoring the CD4+ T-lymphocyte count at least every three months is not possible, initiation of chemoprophylaxis at a CD4+ T-lymphocyte count of greater than 200 but less than 250 per mm³ also should be considered (BII).⁵

Trimethoprim-sulfamethoxazole (TMP-SMZ) is the recommended prophylactic agent (AI).^6-8 One double-strength tablet per day is the preferred regimen (AI).⁷ However, one single-strength tablet per day⁹ is also effective and might be better tolerated (AI). One double-strength tablet three times per week is also effective (BI).¹⁰ TMP-SMZ at a dosage of one double-strength tablet per day confers cross-protection against toxoplasmosis¹¹ and some common respiratory bacterial infections.^7,12 Lower dosages of TMP-SMZ also might confer such protection. In patients who have an adverse reaction that is not life-threatening, treatment with TMP-SMZ should be continued if clinically feasible; in 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 dosage (desensitization) as per published regimens (BI)^13,14 or reintroduction of TMP-SMZ at a reduced dosage or frequency (CIII); up to 70 percent of patients can tolerate such reinstitution of therapy.¹²

If TMP-SMZ cannot be tolerated, prophylactic regimens that can be recommended as alternatives include dapsone (BI),⁷ dapsone plus pyrimethamine plus leucovorin (BI),^15,16 aerosolized pentamidine administered by the Respirgard II nebulizer (Marquest, Englewood, Colo.) (BI),⁸ and atovaquone (BI).^17,18 Atovaquone appears to be as effective as aerosolized pentamidine¹⁸ or dapsone (BI)¹⁷ but is substantially more expensive than the other regimens. In patients seropositive for Toxoplasma gondii who cannot tolerate TMP-SMZ, recommended alternatives to TMP-SMZ for prophylaxis against PCP and toxoplasmosis include dapsone plus pyrimethamine (BI)^15,16 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).

TABLE 2
Prophylaxis to Prevent the First Episode of Opportunistic Disease in Adults and Adolescents with HIV

Preventitive regimens

Pathogen
Indication
First choice
Alternatives

I. Strongly recommended as standard of care

Pneumocystis carinii* CD4+ count <200 per µL or oropharyngeal candidiasis TMP-SMZ, 1 DS orally every day (AI)
TMP-SMZ, 1 SS orally every day (AI) Dapsone, 50 mg orally twice daily or 100 mg orally every day (BI); dapsone, 50 mg orally every day plus pyrimethamine, 50 mg orally every week plus leucovorin, 25 mg orally every week (BI); dapsone, 200 mg orally plus pyrimethamine, 75 mg orally plus leucovorin, 25 mg orally every week (BI); aerosolized pentamidine, 300 mg every mo via Respirgard II nebulizer (BI); atovaquone, 1,500 mg orally every day (BI); TMP-SMZ, 1 DS orally three times weekly (BI)

Mycobacterium tuberculosis

   Isoniazid-sensitive† TST reaction >=5 mm or prior positive TST result without treatment or contact with case of active tuberculosis Isoniazid, 300 mg orally plus pyridoxine, 50 mg orally everyday x 9 mo (AII) or isoniazid, 900 mg orally plus pyridoxine, 100 mg orally twice weekly x 9 mo (BI); rifampin, 600 mg plus pyrazinamide, 20 mg per kg orally every day x 2 mo (AI) Rifabutin, 300 mg orally every day plus pyrazinamide, 20 mg per kg orally every day x 2 mo (BIII); rifampin 600 mg orally every day 3 4 mo (BIII)

   Isoniazid-resistant Same; high probability of exposure to isoniazid-resistant tuberculosis Rifampin 600 mg plus pyrazinamide, 20 mg per kg orally every day x 2 mo (AI) Rifabutin, 300 mg plus pyrazinamide 20 mg per kg orally every day x 2 mo (BIII); rifampin 600 mg orally every day x 4 mo (BIII); rifabutin, 300 mg orally every day x 4 mo (CIII)

   Multidrug- (isoniazid and rifampin) resistant Same; high probability of exposure to multidrug-resistant tuberculosis Choice of drugs requires consultation with public health authorities None

Toxoplasma gondii§ IgG antibody to Toxoplasma and CD4+ count <100 per µL TMP-SMZ, 1 DS orally every day (AII) TMP-SMZ, 1 SS orally every day (BIII); dapsone, 50 mg orally every day plus pyrimethamine, 50 mg orally every week plus leucovorin, 25 mg orally every week (BI); atovaquone, 1,500 mg orally every day with or without pyrimethamine, 25 mg orally every day plusleucovorin, 10 mg orally every day (CIII)

Mycobacterium avium complex¶ CD4+ count <50 per µL Azithromycin, 1,200 mg orally every week (AI), or clarithromycin, 500 mg orally twice daily (AI) Rifabutin, 300 mg orally every day (BI); azithromycin, 1,200 mg orally every week plus rifabutin, 300 mg orally every day (CI)

Varicella zoster virus (VZV) Significant exposure to chickenpox or shingles for patients who have no history of either condition history of either condition or, if available, negative antibody to VZV Varicella zoster immune globulin (VZIG), 5 vials (1.25 mL each) IM, administered <=96 hours after exposure, ideally within 48 hours (AIII)

II. Generally recommended

Streptococcus pneumoniae** All patients Pneumococcal vaccine, 0.5 mL IM (CD4+ >= 200 per mm³ [BII]; CD4+ <200 per mm³ [CIII]--might reimmunize if initial immunization was given when CD4+ <200 per mm³ and if CD4+ increases to>200 mm³ on HAART [CIII]) None

Hepatitis B virus †† All susceptible (anti-HBc-negative) patients Hepatitis B vaccine: 3 doses (BII) None

Influenza virus†† All patients (annually, before influenza season) Whole or split virus, 0.5 mL IM per year (BIII) Rimantadine, 100 mg orally twice daily (CIII), or amantadine, 100 mg orally twice daily (CIII)

Hepatitis A virus†† All susceptible (anti-HAV- negative) patients with chronic hepatitis C Hepatitis A vaccine: two doses (BIII) None

III. Not routinely indicated

Bacteria Neutropenia Granulocyte-colony-stimulating factor (G-CSF), 5 to 10 µg per kg SC every day x 2 to 4 weeks or granulocyte-macrophage colony- stimulating factor (GM-CSF), 250 µg per m² IV over 2 hours every day x 2 to 4 weeks (CII) None

Cryptococcus neoformans§§ CD4+ count <50 per mm³ Fluconazole, 100 to 200 mg orally every day (CI) Itraconazole, 200 mg orally every day (CIII)

Histoplasma capsulatum§§ CD4+ count <100 per mm³, endemic geographic area Itraconazole capsule, 200 mg orally every day (CI) None

Cytomegalovirus (CMV)¶¶ CD4+ count <50 per mm³, and CMV antibody positivity Oral ganciclovir, 1 g orally three times daily (CI) None

NOTE: Information included in these guidelines might not represent U.S. Food and Drug Administration (FDA) approval or approved labeling for the particular products or indications in question. Specifically, the terms "safe" and "effective" might not be synonymous with the FDA-defined legal standards for product approval. The Respirgard II nebulizer is manufactured by Marquest, Englewood, Colo. Letters and Roman numerals in parentheses after regimens indicate the strength of the recommendation and the quality of evidence supporting it (see Table 1).
HIV = human immunodeficiency virus; Anti-HBc = antibody to hepatitis B core antigen; DS = double-strength tablet; HAART = highly active antiretroviral therapy; HAV = hepatitis A virus; mo = month; IM = intramuscular; IV = intravenous; SS = single-strength tablet; TMP-SMZ = trimethoprim-sulfamethoxazole; SC = subcutaneous; TST = tuberculin skin test.
*--Prophylaxis should also be considered for persons with a CD4+ percentage of <14%, for persons with a history of an AIDS-defining illness and, possibly, for those with CD4+ counts >200 but <250 per mm³. TMP-SMZ also reduces the frequency of toxoplasmosis and some bacterial infections. Patients receiving dapsone should be tested for glucose-6 phosphate dehydrogenase deficiency. A dosage of 50 mg every day is probably less effective than one of 100 mg every day. The efficacy of parenteral pentamidine (e.g., 4 mg per kg per month) is uncertain. Fansidar (sulfadoxine-pyrimethamine) is rarely used because of severe hypersensitivity reactions. Patients who are being administered therapy for toxoplasmosis with sulfadiazine-pyrimethamine are protected against Pneumocystis carinii pneumonia and do not need additional prophylaxis against PCP.
†--Directly observed therapy is recommended for isoniazid, 900 mg twice weekly; isoniazid regimens should include pyridoxine to prevent peripheral neuropathy. Rifampin should not be administered concurrently with protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Rifabutin should not be given with hard-gel saquinavir or delavirdine; caution is also advised when the drug is coadministered with soft-gel saquinavir. Rifabutin may be administered at a reduced dosage of 150 mg every day with indinavir, nelfinavir, or amprenavir; at a reduced dosage of 150 mg every other day (or 150 mg three times weekly) with ritonavir; or at an increased dosage of 450 mg every day with efavirenz; information is lacking regarding coadministration of rifabutin with nevirapine. Exposure to multidrug-resistant tuberculosis might require prophylaxis with two drugs; consult public health authorities. Possible regimens include pyrazinamide plus ethambutol or a fluoroquinolone.
§--Protection against toxoplasmosis is provided by TMP-SMZ, dapsone plus pyrimethamine and, possibly, by atovaquone. Atovaquone may be used with or without pyrimethamine. Pyrimethamine alone probably provides little, if any, protection.
¶--See footnote above(†) regarding use of rifabutin with protease inhibitors or nonnucleoside reverse transcriptase inhibitors.
**--Vaccination should be offered to persons who have a CD4+ T-lymphocyte count <200 per mm³, although the efficacy might be diminished. Revaccination 5 years after the first dose or sooner if the initial immunization was given when the CD4+ count was <200 per mm³ and the CD4+ count has increased to >200 per mm³ on HAART is considered optional. Some authorities are concerned that immunizations might stimulate the replication of HIV. However, one study showed no adverse effect of pneumococcal vaccination on patient survival (McNaghten AD, Hanson DL, Jones JL, Dworkin MS, Ward JW, and the Adult/Adolescent Spectrum of Disease Group. Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. AIDS 1999;13:1687-95).
††--These immunizations or chemoprophylactic regimens do not target pathogens traditionally classified as opportunistic but should be considered for use in HIV-infected patients as indicated. Data are inadequate concerning clinical benefit of these vaccines in this population, although it is logical to assume that those patients who develop antibody responses will derive some protection. Some authorities are concerned that immunizations might stimulate HIV replication, although for influenza vaccination, a large observational study of HIV-infected persons in clinical care showed no adverse effect of this vaccine, including multiple doses, on patient survival (J. Ward, Centers for Disease Control and Prevention, personal communication, 1999). Hepatitis B vaccine has been recommended for all children and adolescents and for all adults with risk factors for hepatitis B virus (HBV). Rimantadine and amantadine are appropriate during outbreaks of influenza A. Because of the theoretic concern that increases in HIV plasma RNA following vaccination during pregnancy might increase the risk of perinatal transmission of HIV, providers may wish to defer vaccination until after antiretroviral therapy is initiated. For additional information regarding vaccination against hepatitis A and B and vaccination and antiviral therapy against influenza see: CDC. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1996;45(RR-15); CDC. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1991;40(RR-13); and CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999;48(RR-4).
§§--In a few unusual occupational or other circumstances, prophylaxis should be considered; consult a specialist.
¶¶--Acyclovir is not protective against CMV. Valacyclovir is not recommended because of an unexplained trend toward increased mortality observed in persons with AIDS who were being administered this drug for prevention of CMV disease.

Discontinuation of Primary Prophylaxis. Initial reports from three prospective observational studies,^19-21 one retrospective review²² and one randomized trial²³ suggest that PCP prophylaxis can be safely discontinued in patients responding to HAART with a sustained increase in CD4+ T-lymphocyte counts from less than 200 per mm³ to greater than 200 per mm³. Such reports have mostly included patients receiving primary prophylaxis (no prior episode of PCP) and protease inhibitor-containing regimens. In these studies, median follow-up ranged from six to 12 months, and the median CD4+ T-lymphocyte count at the time prophylaxis was discontinued was greater than 300 per mm³ (300 x 10⁶ per L). At the time PCP prophylaxis was discontinued, many patients had sustained suppression of HIV plasma RNA levels below detection limits of the available assays. Although optimal criteria for discontinuing PCP prophylaxis are still being assessed, providers may wish to discontinue prophylaxis when patients have sustained a CD4+ T-lymphocyte count of greater than 200 per mm³ for at least three to six months (CII). Additional criteria might include sustained reduction in viral load for at least three to six months (CIII).

Restarting Primary Prophylaxis. No data are available to guide recommendations for reinstituting primary prophylaxis. Pending the availability of such data, a reasonable approach would be to use the criteria for initiating prophylaxis.

Children. Children born to HIV-infected mothers should be administered prophylaxis with TMP-SMZ beginning at four to six weeks of age²⁴ (AII). Prophylaxis should be discontinued in 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 10) (AII). The safety of discontinuing prophylaxis in HIV-infected children receiving HAART has not been studied.

Pregnant Women. Chemoprophylaxis for PCP should be administered to pregnant women as in other adults and adolescents (AIII). TMP-SMZ is the recommended prophylactic agent; dapsone is an alternative. Because of theoretic 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, therapy with 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
Initiation of Primary Prophylaxis. Toxoplasma-seropositive patients who have a CD4+ T-lymphocyte count of less than 100 per mm³ (100 x 10⁶ per L) should be administered prophylaxis against toxoplasmic encephalitis (AII).¹¹ The daily double-strength tablet of TMP-SMZ recommended as the preferred regimen for PCP prophylaxis appears to be effective against toxoplasmic encephalitis as well and is therefore recommended (AII).¹¹ If patients cannot tolerate TMP-SMZ, the recommended alternative is dapsone-pyrimethamine, which is also effective against PCP (BI).^15,16 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 toxoplasmic encephalitis and is not recommended (EI).^7,11

Toxoplasma-seronegative persons who are not taking a PCP prophylactic regimen known to be active against toxoplasmic encephalitis should be retested for IgG antibody to Toxoplasma when their CD4+ T-lymphocyte count declines below 100 per mm³ to determine whether they have seroconverted and are therefore at risk for toxoplasmic encephalitis (CIII). Patients who have seroconverted should be administered prophylaxis for toxoplasmic encephalitis as described above (AII).

Discontinuation of Primary Prophylaxis. Limited data suggest that discontinuing prophylaxis in patients whose CD4+ T-lymphocyte counts increase to greater than 100 per mm³ in response to HAART is associated with a low risk for toxoplasmic encephalitis infection. However, the numbers of patients who have been evaluated are insufficient to recommend routine discontinuation of prophylaxis in such patients. Persons whose CD4+ T-lymphocyte count remains less than 200 per mm³ or who have a history of PCP or oropharyngeal candidiasis still require prophylaxis against PCP, as noted previously.

Children. TMP-SMZ, when administered for PCP prophylaxis, also provides prophylaxis against toxoplasmosis. Atovaquone might also provide protection (CIII). Children more than 12 months of age who qualify for PCP prophylaxis and 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 and who are found to be seropositive for Toxoplasma should be administered prophylaxis for PCP and toxoplasmosis (i.e., dapsone plus pyrimethamine) (BIII).

Pregnant Women. TMP-SMZ can be administered for prophylaxis against toxoplasmic encephalitis as described for PCP (AIII). Because of the low incidence of toxoplasmic encephalitis 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 toxoplasmic encephalitis, the health care provider and clinician should be well informed about the benefit of lifelong therapy and the concerns about teratogenicity of pyrimethamine. Most clinicians favor lifelong therapy for the mother, given the high likelihood that disease will recur promptly if therapy is stopped (AIII).

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 toxoplasmic encephalitis) 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).

TABLE 3
Effects of Food on Drugs Used to Prevent Opportunistic Infections

Drug
Food effect
Recommendation

Atovaquone Bioavailability increased up to threefold with high-fat meal. Administer with food.

Ganciclovir (capsules) High-fat meal results in 22% increase in the area under the curve (AUC). Administer with food.

Itraconazole (capsules) Significant increase in bioavailability when taken with a full meal. Grapefruit juice results in 30% decrease in itraconazole AUC. Administer with food; avoid grapefruit juice or increased itraconazole dosage might be necessary.

Itraconazole (solution) 31% increase in AUC when taken under fasting conditions. Take without food if possible.

Cryptosporidiosis
No agents have been proved to be effective as chemoprophylaxis against cryptosporidiosis. Rifabutin or clarithromycin, when taken for Mycobacterium avium complex prophylaxis, were associated with a reduced risk for cryptosporidiosis in one study,²⁵ but data are insufficient to warrant a recommendation for using these drugs.

Children. 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).

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

Tuberculosis
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, there are selected situations in which anergy evaluation might assist in guiding individual decisions about preventive therapy.²⁶

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

All HIV-infected persons, regardless of age, who have a positive TST result but no evidence of active tuberculosis and no history of treatment or prophylaxis for tuberculosis should be administered preventive chemotherapy. Options include isoniazid daily (AII) or twice weekly (BI) for nine months or two months of therapy with rifampin and pyrazinamide (AI) or rifabutin and pyrazinamide (BIII).²⁶ 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 rifampin or rifabutin should be made after careful consideration of potential drug interactions, especially those related to protease inhibitors and nonnucleoside reverse transcriptase inhibitors (see Drug Interactions below). Directly observed therapy should be used with intermittent dosing regimens (AI) and when otherwise operationally feasible (BIII).²⁶

HIV-infected persons who are close contacts of persons who have infectious tuberculosis should be administered preventive therapy--regardless of their TST results, age or prior courses of chemoprophylaxis--after the diagnosis of active tuberculosis has been excluded (AII).²⁶ In addition to household contacts, such persons might also include contacts in the same drug treatment or health care facility, coworkers and other contacts if transmission of tuberculosis is demonstrated.

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

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

Although the reliability of the TST might diminish as the CD4+ T-lymphocyte count declines, annual repeat testing should be considered for HIV-infected persons who are TST-negative on initial evaluation and who belong to populations in which there is a substantial risk for exposure to M. tuberculosis (BIII). Clinicians also may consider repeating TSTs for persons whose immune function has improved because of HAART (i.e., those whose CD4+ T-lymphocyte count has increased to greater than 200 per mm³) (CIII). In addition to confirming tuberculous infection, TST conversion in an HIV-infected person should alert health care providers to the possibility of recent M. tuberculosis transmission and should prompt notification of public health officials for investigation to identify a possible source case.

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

Drug Interactions. Rifampin should not be administered with protease inhibitors or nonnucleoside reverse transcriptase inhibitors (EI).²⁶ Rifabutin is an acceptable alternative but should not be used with the protease inhibitor hard-gel saquinavir; caution is also advised if the drug is coadministered with soft-gel saquinavir, but data are lacking. Rifabutin can be administered at one half the usual daily dosage (i.e., reduce from 300 mg to 150 mg per day) with indinavir, nelfinavir or amprenavir, or with one fourth the usual dosage (i.e., 150 mg every other day or three times a week) with ritonavir. Similarly, rifabutin should not be used with the nonnucleoside reverse transcriptase inhibitor delavirdine. Pharmacokinetic data suggest that rifabutin at an increased dosage can be administered with efavirenz; a dosage of 450 mg per day has been suggested.²⁶ Information is lacking regarding coadministration of rifabutin with nevirapine.

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

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

TABLE 4
Effects of Medications on Drugs Used to Prevent Opportunistic Infections

Affected drug
Interacting drugs
Mechanism/effect
Recommendation

Atovaquone Rifampin Induction of metabolism--decreased drug levels Concentrations might not be therapeutic; avoid combination or increase atovaquone dose.

Clarithromycin Ritonavir Inhibition of metabolism--increased drug levels by 77% No adjustment needed in normal renal function; adjust if creatinine clearance is < 30.

Clarithromycin Nevirapine Induction of metabolism--decrease in clarithromycin area under the curve (AUC) by 35%, increase in AUC of 14-OH clarithromycin by 27% Effect on Mycobacterium avium prophylaxis might be decreased; monitor closely.

Ketoconazole Antacids, didanosine, histamine H₂-receptor blockers, proton pump inhibitors Increase in gastric pH that impairs absorption of ketoconazole Avoid use of ketoconazole with pH-raising agents or use alternative antifungal drug.

Quinolone antibiotics (ciprofloxacin, levofloxacin, ofloxacin) Didanosine, antacids, iron products, calcium products, sucralfate Chelation that results in marked decrease in quinolone drug levels Administer interacting drug at least 2 hours after quinolone.

Rifabutin Fluconazole Inhibition of metabolism--marked increase in rifabutin drug levels Monitor for rifabutin toxicity such as uveitis, nausea and neutropenia.

Rifabutin Efavirenz Induction of metabolism--significant decrease in rifabutin AUC Increase rifabutin dosage to 450 mg daily.

Rifabutin Ritonavir, saquinavir, indinavir, nelfinavir, amprenavir, delavirdine Inhibition of metabolism--marked increase in rifabutin drug levels Contraindicated with hard-gel saquinavir (caution also advised with soft-gel saquinavir) and delavirdine; use 1/2 dosage (150 mg daily) with indinavir, nelfinavir, amprenavir; use 1/4 dosage (150 mg every other day) with ritonavir.

Disseminated Infection with Mycobacterium avium Complex
Initiation of Primary Prophylaxis. Adults and adolescents who have HIV infection should receive chemoprophylaxis against disseminated Mycobacterium avium-complex (MAC) disease if they have a CD4+ T-lymphocyte count of less than 50 per mm³ (50 x 10⁶ per L) (AI).²⁷ Preferred prophylaxis is clarithromycin^28,29 or azithromycin³⁰ (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).²⁸ 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).³⁰ In addition to their preventive activity for MAC disease, clarithromycin and azithromycin each confer protection against respiratory bacterial infections (BII). If clarithromycin or azithromycin cannot be tolerated, rifabutin is an alternative prophylactic agent for MAC disease (BI)^28,30,31 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 Drug Interactions, below). Before prophylaxis is initiated, disseminated MAC disease should be ruled out by clinical assessment, which might include obtaining a blood culture for MAC if warranted. Because treatment with rifabutin could result in the development of resistance to rifampin in persons who have active tuberculosis, active tuberculosis should also be excluded before rifabutin is used for prophylaxis.

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

Discontinuation of Primary Prophylaxis. Information from observational studies^22,32 suggested a low rate of disseminated infection with MAC among persons who responded to HAART with an increase in CD4+ T-lymphocyte count from less than 50 per mm³ to greater than 100 per mm³. Although the optimal criteria for discontinuing MAC prophylaxis remain to be defined, a reasonable option would be to consider discontinuing prophylaxis in patients with a CD4+ T-lymphocyte count of greater than 100 per mm³ for a sustained period (e.g., greater than three to six months) and sustained suppression of HIV plasma RNA for a similar period (CII).

Restarting Primary Prophylaxis. No data are available on which to base recommendations for reinstituting prophylaxis. Pending the availability of such data, a reasonable approach would be to use the criteria for initiating MAC prophylaxis (CIII).

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

Children. HIV-infected children less than 13 years of age 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 6 years of age or more, less than 50 per mm³

Children two to six years of age, less than 75 per mm³

Children one to two years of age, less than 500 per mm³

Children less than 12 months of age, less than 750 per mm³ (750 x 10⁶ per L) (AII).

For the same reasons that clarithromycin and azithromycin are the preferred prophylactic agents in adults, they should also be considered for children (AII); oral suspensions of both agents are commercially available in the United States. No liquid formulation of rifabutin suitable for pediatric use is commercially available in the United States. The safety of discontinuing MAC prophylaxis in children whose CD4+ T-lymphocyte counts have increased in response to HAART has not been studied.

Pregnant Women. Chemoprophylaxis for MAC disease should be administered to pregnant women as in 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).³³ Experience with rifabutin is limited. Clarithromycin has been demonstrated to be a teratogen in animals and should be used with caution during pregnancy.³⁴ For secondary prophylaxis (chronic maintenance therapy), azithromycin plus ethambutol are the preferred drugs (BIII).

TABLE 5
Effects of Opportunistic Infection Medications on Drugs Commonly Administered to Persons Infected with HIV

Affected drug
Interacting drugs
Mechanism/effect
Recommendation

Indinavir, saquinavir, ritonavir, nelfinavir, amprenavir Rifampin Induction of metabolism--marked decrease in protease inhibitor drug levels Avoid concomitant use.

Delavirdine, nevirapine, efavirenz Rifampin Induction of metabolism--marked decrease in drug levels Avoid concomitant use.

Saquinavir (hard-gel), delavirdine Rifabutin Induction of metabolism--marked decrease in drug levels Avoid concomitant use.

Terfenadine, astemizole, cisapride Ketoconazole, itraconazole, fluconazole, clarithromycin Inhibition of metabolism Cardiotoxic life-threatening effects possible; avoid concomitant use.

Didanosine (ddI) Ganciclovir Increases ddI area under the curve by approximately 100% Clinical significance unknown; monitor for ddI-related adverse effects.

HIV = human immunodeficiency virus.

Bacterial Respiratory Infections
As soon as feasible after HIV infection is diagnosed, adults and adolescents who have a CD4+ T-lymphocyte count of 200 per mm³ or more should be administered a single dose of 23-valent polysaccharide pneumococcal vaccine if they have not had this vaccine during the previous five years (BII).^35,36 For persons who have a CD4+ T-lymphocyte count of less than 200 per mm³, vaccination can be offered, although the humoral response and clinical efficacy are likely to be diminished (CIII).

The recommendation to vaccinate is increasingly pertinent because of the increasing incidence of invasive infections with drug-resistant (including TMP-SMZ-, macrolide-, penicillin- and beta-lactamresistant) strains of Staphylococcus pneumoniae. Limited data suggest that administration of certain bacterial vaccines might transiently increase HIV replication and plasma HIV-1 RNA levels in a minority of HIV-infected persons. However, there is no evidence that adverse clinical outcomes are associated with this transient increase. Most experts believe that the benefit of pneumococcal vaccination outweighs the potential risk.

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.³⁷ In addition, revaccination one time should also be considered if the initial vaccination was given when the CD4+ T-lymphocyte count was less than 200 per mm³ and if the CD4+ T-lymphocyte count has increased to greater than 200 per mm³ as a result of HAART (CIII).

The incidence of Haemophilus influenzae type b infection in adults is low. Therefore, H. influenzae type b vaccine is not generally 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 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 possibility 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).

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, by stopping myelosuppressive drugs (CII) or by administering granulocyte-colony-stimulating factor (G-CSF) (CII).

Children. Children who have HIV infection should be administered H. influenzae type b vaccine in accordance with the guidelines of the Advisory Committee on Immunization Practices³⁸ and the American Academy of Pediatrics³⁹ (AII). Children more than two years of age also should be administered 23-valent polysaccharide pneumococcal vaccine (BII). Revaccination with pneumococcal vaccine generally should be offered after three to five years to children less than 10 years of age and after five years to children 10 years of age or older (BIII).

To prevent serious bacterial infections in HIV-infected children who have hypogammaglobulinemia (IgG less than 400 mg per dL), clinicians should use intravenous immunoglobulin (IVIG) (AI). Respiratory syncytial virus (RSV) IVIG (in a dosage of 750 mg per 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.

Pregnant Women. 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, vaccination may be deferred when feasible, until after antiretroviral therapy has been initiated to prevent perinatal HIV transmission (CIII).

TABLE 6
Adverse Effects of Opportunistic Infection Medications Used in the Management of HIV Infection

Bone marrow suppression Cidofovir, dapsone, ganciclovir, pyrimethamine, rifabutin, sulfadiazine, trimethoprim- sulfamethoxazole, trimetrexate

Diarrhea Atovaquone, clindamycin

Hepatotoxicity Clarithromycin, fluconazole, isoniazid, itraconazole, ketoconazole, pyrazinamide, rifabutin, rifampin

Nephrotoxicity Amphotericin B, cidofovir, foscarnet, pentamidine

Ocular effects Cidofovir, ethambutol, rifabutin

Pancreatitis Pentamidine, trimethoprim-sulfamethoxazole

Peripheral neuropathy Isoniazid

Skin rash Atovaquone, dapsone, sulfadiazine, trimethoprim-sulfamethoxazole

HIV = human immunodeficiency virus.

Bacterial Enteric Infections
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 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 (in a dosage of 500 mg per day) can be considered when prophylaxis is deemed necessary (BIII). As an alternative (e.g., in 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.

Antimicrobial agents such as fluoroquinolones should be given to patients before their departure, with directions to be taken empirically (e.g., 500 mg of ciprofloxacin twice a day for three to seven days) should traveler's diarrhea develop (BIII). Fluoroquinolones should be avoided in children less than 18 years of age and in pregnant women, and alternative antibiotics should be considered (BIII).

Travelers should consult a physician if the diarrhea is severe and does not respond to empiric therapy, if the stools contain blood, if fever is accompanied by shaking chills or if dehydration develops. Antiperistaltic agents (e.g., diphenoxylate and loperamide) can be used to treat mild diarrhea. However, the use of these drugs should be discontinued if symptoms persist beyond 48 hours. Moreover, these agents should not be administered to patients who have a high fever or who have blood in the stool (AII).

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 (in a dosage of 750 mg twice a day for 14 days)--can be used when antimicrobial therapy is chosen (CIII).

Children. 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).

HIV-exposed infants less than three months of age 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.

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. Antiperistaltic drugs are not recommended for children (DIII).

Pregnant Women. Because pregnancy and HIV infection confer a risk for listeriosis, pregnant HIV-infected women should heed recommendations regarding listeriosis (BII).

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 infection, pregnant women with Salmonella gastroenteritis should receive treatment (BIII). Choices for treatment include ampicillin, cefotaxime, ceftriaxone or TMP-SMZ. Fluoroquinolones should be avoided.

Fluoroquinolones should not be used during pregnancy. TMP-SMZ might offer some protection against traveler's diarrhea.

Infection with Bartonella (Formerly Rochalimaea)
No data support chemoprophylaxis for Bartonella-associated disease (CIII).

Children. The risks of cat ownership for HIV-infected children who are severely immunocompromised should be discussed with parents and caretakers (CIII).

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

TABLE 7
Dosages of Drugs for Primary Prevention or Maintenance Therapy for Persons with Opportunistic Infections and Renal Insufficiency

Drug
Normal dosage
CrCl (mL/min/1.73 m²)
Adjusted dosage

Acyclovir 200 mg orally three times daily <10 200 mg every 12 hours

400 mg orally every 12 hours <10 200 mg every 12 hours

800 mg orally every 4 hours 10 to 25 800 mg every 8 hours

800 mg orally every 4 hours <10 800 mg every 12 hours

Cidofovir 5 mg per kg IV every other week (with probenecid) Increase in serum creatinine of 0.3 to 0.4 above baseline 3 mg per kg

Increase in serum creatinine of 0.5 above baseline or 3+ proteinuria Discontinue

Ciprofloxacin 500 mg orally every 12 hours 30 to 50 250 to 500 mg every 12 hours

<30 250 to 500 mg every 18 hours

Clarithromycin 500 mg twice daily <30 1/2 dose (or double interval)

Famciclovir 500 mg orally every 12 hours 20 to 39 250 mg every 12 hours

<20 250 mg every 24 hours

Fluconazole 50 to 400 mg orally every day 10 to 50 1/2 dose

<10 1/4 dose

Dialysis Full dose after dialysis

Foscarnet 90 to 120 mg per kg IV every day

CrCl*:

>1.4
1.0 to 1.4
0.8 to 1.0
0.6 to 0.8
0.5 to 0.6
0.4 to 0.5
<0.4

Low dose:

90 mg every 24 hours
70 mg every 24 hours
50 mg every 24 hours
80 mg every 48 hours
60 mg every 48 hours
50 mg every 48 hours
Not recommended

High dose:

120 mg every 24 hours
90 mg every 24 hours
65 mg every 24 hours
105 mg every 48 hours
80 mg every 48 hours
65 mg every 48 hours
Not recommended

Ganciclovir Oral: 1 g orally three times daily 50 to 69 1,500 mg every day or 500 mg three times daily

25 to 49 1,000 mg every day or 500 mg twice daily

10 to 24 500 mg every day

<10 500 mg three times weekly after dialysis

IV: 5 mg per kg every day or 6 mg per kg every day x 5 days per week 50 to 69 2.5 mg per kg every 24 hours

25 to 49 1.25 mg per kg every 24 hours

10 to 24 0.625 mg per kg every 48 hours

<10 0.625 mg per kg three times weekly

TMP-SMZ 1 DS every day
1 DS three times weekly
1 SS every day <30 1/2 dose

CrCl = creatinine clearance; TMP-SMZ = trimethoprim-sulfamethoxazole; DS = double-strength tablet; IV = intravenous; SS = single-strength tablet.
*--Creatinine clearance for foscarnet is expressed as mL per min per kg.

Candidiasis
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.^40-42 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).

Children. Primary prophylaxis of candidiasis in HIV-infected infants is not indicated (DIII).

Pregnant Women. 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.^34,43 In addition, itraconazole is embryotoxic and teratogenic in animal systems.⁴⁴ 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 therapy with azoles should be discontinued in 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
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).

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 dosages of 100 to 200 mg daily is reasonable in patients whose CD4+ T-lymphocyte counts are less than 50 per mm³ (CI).^40-42

Pregnant Women. 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).^43-45 In patients who conceive while being administered primary prophylaxis and who elect to continue their pregnancy, prophylaxis should be discontinued.

TABLE 8
Wholesale Acquisition Costs of Agents Recommended for the Prevention of Opportunistic Infections in Adults Infected with HIV

Opportunistic pathogen
Drug/vaccine
Dose
Annual cost * per patient

Pneumocystis carinii Trimethoprim-sulfamethoxazole 160/800 mg every day $60

Dapsone 100 mg every day 72

Aerosolized pentamidine 300 mg every month 1,185

Atovaquone 1,500 mg every day 10,647

Mycobacterium avium complex Clarithromycin 500 mg twice daily 2,347

Azithromycin 1,200 mg once weekly 1,635

Rifabutin 300 mg every day 3,352

Cytomegalovirus Ganciclovir (oral) 1,000 mg three times daily 17,269

Ganciclovir implant† 5,000

Ganciclovir (IV) 5 mg per kg every day 9,113

Foscarnet (IV) 90 to 120 mg per kg every day 27,960 to 36,770

Cidofovir (IV) 375 mg every other week 19,812

Fomivirsen (intravitreal) 1 vial every 4 weeks 12,000

Mycobacterium tuberculosis Isoniazid§ 300 mg every day 23

Rifampin 600 mg every day 1,540

Pyrazinamide 1,500 mg every day 1,005

Ethambutol 900 mg every day 1,527

Fungi Fluconazole 200 mg every day 4,267

Itraconazole (capsules) 200 mg every day 4,893

Itraconazole (solution) 200 mg every day 5,129

Ketoconazole 200 mg every day 1,230

Herpes simplex virus Acyclovir 400 mg twice daily 1,300

Famciclovir 500 mg twice daily 4,826

Valacyclovir 500 mg twice daily 1,435

Toxoplasma gondii Pyrimethamine 50 mg once weekly 45

Leucovorin 25 mg once weekly 1,248

Sulfadiazine 500 mg four times daily 1,421

Streptococcus pneumoniae 23-valent pneumococcal vaccine 0.5 mL IM once 13

Influenza virus Influenza vaccine 0.5 mL IM once 5

Hepatitis B virus Recombinant hepatitis B 10 to 20 µg IM 3 3 195

Hepatitis A virus Hepatitis A vaccine 1.0 mL IM 3 2 120

Bacterial infections G-CSF 300 µg three times weekly 25,780

Varicella zoster virus VZIG 5 vials (6.25 mL) 560

HIV = human immunodeficiency virus; G-CSF = granulocytecolony-stimulating factor; IV = intravenous; IM = intramuscular; VZIG = varicella zoster immune globulin.
*--Estimated cost to the pharmacist based on average wholesale prices in Red book. Montvale, N.J.: Medical Economics Data, 1999. Cost to the patient will be higher, depending on prescription filling fee.
†--Implant generally lasts 6 to 9 months.
§--Cost for 9 months of therapy.

Histoplasmosis
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).

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 areas where Histoplasma capsulatum is endemic.⁴⁶ 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 per mm³ who are at especially high risk because of occupational exposure or who live in a community with a hyperendemic rate of histoplasmosis (10 or more cases per 100 patient-years) (CI).

Children. 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. Because of the embryotoxicity and teratogenicity of itraconazole in animal systems, primary prophylaxis against histoplasmosis should not be offered during pregnancy (DIII).

Coccidioidomycosis
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).

Primary prophylaxis for HIV-infected persons who live in coccidioidomycosis-endemic areas is not routinely recommended.

TABLE 9
Criteria for Discontinuing and Restarting Opportunistic Infection Prophylaxis for Adults with HIV Infection*

Opportunistic illness
Primary criteria for discontinuing prophylaxis
Secondary criteria for discontinuing prophylaxis
Criteria for restarting prophylaxis

Pneumocystic carinii pneumonia CD4+ 200 cells per mm³ for >3 to 6 months (CII) No criteria recommended for stopping Same as criteria for initiating (CIII)

Disseminated Mycobacterium avium complex CD4+ >100 per mm³ for > 3 to 6 months; sustained suppression of HIV plasma RNA (CII) No criteria recommended for stopping Same as criteria for initiating (CIII)

Toxoplasmosis No criteria recommended for stopping No criteria recommended for stopping Not applicable

Cryptococcosis Not applicable No criteria recommended for stopping Not applicable

Histoplasmosis Not applicable No criteria recommended for stopping Not applicable

Coccidioidomycosis Not applicable No criteria recommended for stopping Not applicable

Cytomegalovirus retinitis Not applicable CD4+ >100 to 150 per mm³ for >3 to 6 months

Durable suppression of HIV plasma RNA
Non-sight-threatening lesion
Adequate vision in contralateral eye
Regular ophthalmic examinations (CIII) Restart maintenance when CD4+ <50 to 100 per mm³ (CIII)

HIV = human immun