Opportunistic Infection Prophylaxis

Background

Prophylaxis against an opportunistic infection (OI) is treatment given to HIV-infected individuals to prevent either a first episode of an OI (primary prophylaxis) or the recurrence of an OI (secondary prophylaxis). Prophylaxis is recommended to prevent three important OIs: Pneumocystis jiroveci pneumonia (PCP), Mycobacterium avium complex (MAC), and toxoplasmosis. Prophylaxis also is recommended to prevent tuberculosis (TB) in patients with latent Mycobacterium tuberculosis infection (see chapter Latent Tuberculosis Infection). In endemic regions, prophylaxis against Histoplasma capsulatum and Coccidioides species is advised. And in some situations, prophylaxis against other OIs may be reasonable; see the OI prevention recommendations of the U.S. Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association (reference below) for additional information.

Pneumocystis jiroveci Pneumonia

Background

PCP remains the most common life-threatening infection among U.S. residents with advanced HIV disease.

Primary Prophylaxis: Indications

  • Prophylaxis should be administered to all HIV-infected patients with a CD4 count of <200 cells/µL, a history of an AIDS-defining illness, or a history of oral thrush. PCP prophylaxis also is indicated for patients with CD4 counts of >200 cells/µL in the presence of a CD4 percentage <14%.
  • For patients whose CD4 counts are declining toward 200 cells/µL, the CD4 count should be monitored closely. PCP prophylaxis should be considered for patients with a CD4 count of 200-250 cells/µL if laboratory monitoring will not be possible within 3 months.

Prophylaxis Options: Recommended Regimens

  • Trimethoprim-sulfamethoxazole (TMP-SMX) (also known as cotrimoxazole, Bactrim, and Septra) 1 double-strength (DS) tablet PO QD (Note: This regimen also is effective in preventing toxoplasmosis.)
  • TMP-SMX 1 single-strength tablet PO QD (this lower-dose regimen may be better tolerated) (Note: This also is likely to be effective in preventing toxoplasmosis.)
    • Warning: Many patients have adverse reactions to sulfa medications. Severe reactions may include persistent neutropenia, rash (including severe erythroderma), and Stevens-Johnson syndrome (bullae and desquamation of the skin). For patients with milder reactions, chemoprophylaxis with TMP-SMX should be continued if clinically possible. Some patients with a history of serious adverse reaction may undergo desensitization, but this must be done cautiously and it requires diligence from the patient and careful management by the provider (see chapter Sulfa Desensitization).

Prophylaxis Options: Alternative Regimens

Other options for prophylaxis include the following:

  • TMP-SMX DS, 1 tablet TIW (e.g., Monday, Wednesday, and Friday) (Note: This regimen also is likely to be effective in preventing toxoplasmosis.)
  • Dapsone 100 mg PO QD or 50 mg PO BID (Note: These regimens do not prevent toxoplasmosis.)
  • Dapsone 50 mg PO QD + pyrimethamine 50 mg PO once weekly + leucovorin 25 mg PO once weekly (Note: This regimen also is effective in reducing the risk of toxoplasmosis.)
    • Warning: Glucose-6-phosphate dehydrogenase (G6PD) deficiency can increase the risk of hemolytic anemia or methemoglobinemia in patients receiving dapsone. Screen for G6PD deficiency before starting dapsone. (G6PD deficiency is found in approximately 10% of African-American males, and in 1-2% of males of Mediterranean, Indian, and Asian descent.)
  • Dapsone 200 mg PO once weekly + pyrimethamine 75 mg PO once weekly + leucovorin 25 mg PO once weekly
  • Aerosolized pentamidine 300 mg once per month, via Respirgard II nebulizer (Note: This regimen does not prevent toxoplasmosis.)
    • Warning: Aerosolized pentamidine may increase the risk of extrapulmonary pneumocystosis, pneumothorax, and bronchospasm. It increases the risk of TB transmission to others if the patient has active pulmonary tubercular disease, unless ventilation (negative-pressurized facility with outside venting) is adequate. Do not use for patients in whom TB is suspected. The availability of treatment facilities offering aerosolized pentamidine may be limited.
  • Atovaquone 1,500 mg QD (Note: This also is effective in reducing the risk of toxoplasmosis.) Atovaquone is more expensive than dapsone. It should be taken with high-fat meals for optimal absorption.
  • Atovaquone 1,500 mg + pyrimethamine 25 mg + folinic acid 10 mg, all taken PO QD (Note: This regimen also is effective in reducing the risk of toxoplasmosis.)

Secondary Prophylaxis Indications

Prophylaxis should be given to all patients with a history of PCP.

Discontinuing Prophylaxis

Primary or secondary prophylaxis can be discontinued if the CD4 count has increased to ≥200 cells/µL for at least 3 months in response to effective antiretroviral therapy (ART), with the following cautions:

  • If the patient had PCP in the past and the episode of PCP occurred at a CD4 count of >200 cells/µL, it may be prudent to continue PCP prophylaxis for life, regardless of how high the CD4 count rises as a consequence of ART.
  • PCP prophylaxis should be reinitiated if the CD4 count decreases to <200 cells/µL or the patient meets other criteria as indicated above.

Prophylaxis During Pregnancy

TMP-SMX is the recommended agent for use during pregnancy; dapsone may be used as an alternative. Some experts recommend high-dose folate supplementation (e.g., 4 mg daily) for pregnant women receiving TMP-SMX, because TMP-SMX may worsen folate deficiency; however, this may increase risk of TMP-SMX failure; if high-dose folate supplementation is given, it should be limited to the first trimester. Prophylaxis that includes pyrimethamine generally should be deferred until after pregnancy. During the first trimester, aerosolized pentamidine (which is not systemically absorbed) can be used if the potential teratogenicity of oral agents is a concern.

Mycobacterium avium Complex

Background

MAC is common among patients with advanced HIV disease and it generally occurs in people with CD4 counts of <50 cells/µL.

Primary Prophylaxis: Indications

Prophylaxis should be administered to all HIV-infected patients with CD4 counts of <50 cells/µL. Before starting prophylaxis, rule out active MAC infection by clinical assessment and, if warranted, by acid-fast bacilli (AFB) blood cultures (see chapter Mycobacterium avium Complex Disease). Also rule out active TB prior to starting any rifabutin-containing regimen for MAC prophylaxis. Review the current drug regimen for medications that may interact with MAC prophylaxis.

Prophylaxis Options: Recommended Regimens

  • Azithromycin 1,200 mg PO weekly
  • Clarithromycin 500 mg PO BID (Note: Clarithromycin is not recommended for use during pregnancy, and it can have significant interactions with efavirenz, atazanavir, and other drugs; see chapter Drug-Drug Interactions with HIV-Related Medications.)
  • Azithromycin 600 mg PO BIW

Prophylaxis Options: Alternative Regimens

Rifabutin 300 mg QD (Note: Rifabutin has significant interactions with many drugs; certain nonnucleoside reverse transcriptase inhibitors and protease inhibitors should be avoided or dosage adjustment of rifabutin may be required. See chapter Drug-Drug Interactions with HIV-Related Medications.)

Secondary Prophylaxis

Patients should receive lifelong chronic maintenance therapy, unless immune reconstitution occurs in response to ART. See chapter Mycobacterium avium Complex Disease.

Discontinuing Prophylaxis

Primary prophylaxis for MAC can be discontinued in persons who have responded to effective ART with sustained increases in CD4 counts to >100 cells/µL for at least 3 months. Careful observation and monitoring are required, and prophylaxis should be restarted if the patient's CD4 count decreases to <50 cells/µL.

Secondary prophylaxis can be discontinued in patients who received at least 12 months of treatment for MAC, are asymptomatic, and have sustained (for at least 6 months) CD4 counts of >100 cells/µL on ART. Secondary prophylaxis should be reintroduced if the CD4 count decreases to <100 cells/µL.

Prophylaxis During Pregnancy

Azithromycin is the prophylactic drug of choice during pregnancy, although evidence for its safety in the first trimester is limited. Clarithromycin is teratogenic in animals.

Toxoplasmosis

Background

Toxoplasmic encephalitis (TE) usually is caused by reactivation of latent Toxoplasma gondii infection in patients with advanced immunosuppression (especially those with CD4 counts of <100 cells/µL). The CDC/NIH recommendations state that all HIV-infected patients should be tested for Toxoplasma immunoglobulin G (IgG) antibody soon after the diagnosis of HIV infection. Toxoplasma IgG-negative patients should be counseled to avoid sources of infection (see chapter Preventing Exposure to Opportunistic and Other Infections), and should be retested for Toxoplasma IgG if CD4 counts fall to <100 cells/µL to determine whether they have seroconverted and are therefore at risk of TE. (See chapter Toxoplasmosis for more information on active disease and secondary prophylaxis.)

Primary Prophylaxis: Indications

Prophylaxis should be administered to all HIV-infected patients with CD4 counts of <100 cells/µL who are seropositive for Toxoplasma. IgG-negative patients should avoid exposure to Toxoplasma; see "Patient Education," below, and chapter Preventing Exposure to Opportunistic and Other Infections.

Prophylaxis Options: Recommended Regimens

  • TMP-SMX DS, 1 tablet QD (Note: This option also is effective in preventing PCP.)

Prophylaxis Options: Alternative Regimens

(Note: The following options also are effective in preventing PCP.)

  • TMP-SMX DS, 1 tablet PO TIW
  • TMP-SMX single strength, 1 tablet PO QD
  • Dapsone 50 mg PO QD + pyrimethamine 50 mg PO weekly + folinic acid 25 mg PO weekly
  • Dapsone 200 mg PO weekly + pyrimethamine 75 mg PO weekly + folinic acid 25 mg PO weekly
    • Warning: G6PD deficiency can increase the risk of hemolytic anemia or methemoglobinemia in patients receiving dapsone. Screen for G6PD deficiency before starting dapsone. (G6PD deficiency is found in approximately 10% of African-American males, and in 1-2% of males of Mediterranean, Indian, and Asian descent.)
  • Atovaquone 1,500 mg PO QD, with or without pyrimethamine 25 mg PO QD + folinic acid 10 mg PO QD (This alternative is quite expensive.)
  • Neither aerosolized pentamidine nor dapsone alone provides protection
    against TE.

Secondary Prophylaxis

Patients should receive lifelong chronic maintenance therapy, unless immune reconstitution occurs in response to ART (see chapter Toxoplasmosis).

Discontinuing Prophylaxis

Primary prophylaxis for TE can be discontinued in patients who have responded to effective ART with sustained CD4 counts of >200 cells/µL for at least 3 months. CD4 counts should be monitored carefully, and prophylaxis should be restarted in patients whose CD4 counts decrease to <100-200 cells/µL.

Secondary prophylaxis may be discontinued if TE signs and symptoms have resolved with treatment and if patients have sustained (for at least 6 months) CD4 counts of >200 cells/µL on ART. Secondary prophylaxis should be reintroduced if CD4 counts drop to <200 cells/µL.

Prophylaxis During Pregnancy

TMP-SMX may be used as primary prophylaxis during pregnancy. Risks of TMP-SMX in the first trimester must be balanced against the risks of reactivated toxoplasmosis. Some experts recommend high-dose folate supplementation (e.g., 4 mg QD) for pregnant women receiving TMP-SMX, because TMP-SMX may worsen folate deficiency; however, this may increase risk of TMP-SMX failure; if high-dose folate supplementation is given, it should be limited to the first trimester. Pyrimethamine has been associated with birth defects in animal studies, but limited data in human studies have not shown an increased risk; guidelines support its use after the first trimester. Secondary prophylaxis generally should be provided using the same guidelines as for nonpregnant women.

Histoplasmosis

Background

Infection with Histoplasma capsulatum is common in several geographic areas, including the Ohio and Mississippi River Valleys as well as parts of Central and South America, Asia, and Africa. Symptomatic disease can occur via primary infection or reactivation of previously silent infection in the setting of waning cellular immunity. CD4 counts of ≤150 cells/µL, along with positive Histoplasma serology and environmental exposure, are associated with increased risk of symptomatic disease. Histoplasmosis can cause a range of clinical manifestations including respiratory, gastrointestinal, central nervous system (CNS), and cutaneous disease.

Primary Prophylaxis: Indications

Prophylaxis can be considered for HIV-infected patients with CD4 counts of ≤150 cells/µL who are at high risk because of occupational exposure and for those who live in an area where histoplasmosis is highly endemic. HIV-infected patients with CD4 counts of ≤150 cells/µL should be educated to avoid exposure.

Prophylaxis Options: Recommended Regimens

  • Itraconazole 200 mg PO QD (Note: Itraconazole has significant interactions with many drugs, including nonnucleoside reverse transcriptase inhibitors, protease inhibitors, and maraviroc. Dosage adjustments may be required, and some combinations may be contraindicated; consult with a pharmacist or other specialist.)

Secondary Prophylaxis

Patients with a history of severe disseminated disease or CNS infection and those who have relapsed despite receiving appropriate therapy should receive long-term suppressive therapy.

Discontinuing Prophylaxis

Primary prophylaxis can be discontinued once CD4 counts are ≥150 cells/µL for at least 6 months. CD4 counts should be monitored carefully, and prophylaxis should be restarted for patients whose CD4 counts decrease to <150 cells/µL.

Secondary prophylaxis may be discontinued if patients have received at least 1 year of itraconazole, have negative blood cultures, have had CD4 counts of ≥150 cells/µL for at least 6 months on ART, and have serum Histoplasma antigen <2 units. Suppressive therapy should be restarted for patients whose CD4 counts decrease to <150 cells/µL.

Prophylaxis During Pregnancy

Azoles should be avoided during pregnancy, especially during the first trimester, because of teratogenicity concerns.

Coccidiomycosis

Background

The Coccidioides species fungus is endemic to many arid regions. In the United States, it is found primarily in the Sonoran Desert in Arizona and the San Joaquin "Central" Valley in California, but also in areas of New Mexico, western Texas, Nevada, and Utah. It also is endemic to many arid regions in Central and South America. Immune response to Coccidioides species declines as CD4 counts decrease, and risk of developing symptomatic disease in endemic areas is increased when the CD4 count is <250 cells/µL. In HIV-infected patients, six syndromes have been described: focal pneumonia, diffuse pneumonia, cutaneous involvement, meningitis, liver or lymph node involvement, and positive serology without localized infection.

Primary Prophylaxis: Indications

  • Primary prophylaxis is not beneficial and is not recommended. Patients in endemic areas cannot avoid Coccidioides but should be educated to avoid extensive exposure (e.g., through disturbed soil and dust storms). Annual monitoring for seroconversion of HIV-infected patients in endemic areas is reasonable; in patients with CD4 counts of <250 cells/µL who develop a new positive IgM or IgG, antifungal therapy is recommended to preempt active disease (fluconazole 400 mg PO QD).

Secondary Prophylaxis

Patients who have completed initial treatment for coccidiomycosis should receive lifelong suppressive therapy.

Discontinuing Prophylaxis

Patients with a history of meningeal disease should be treated with suppressive therapy for life, as they are at high risk of relapse. Patients with a history of diffuse pulmonary disease or nonmeningeal disseminated infection also are at high risk of relapse; consult with experts. Patients with focal coccidioidal pneumonia who have had good clinical response to antifungals can discontinue secondary prophylaxis once they have received 12 months of therapy, and have CD4 counts of >250 cells/µL on ART. These patients should undergo close radiologic and serologic monitoring for recurrence.

Prophylaxis During Pregnancy

Women who acquire coccidiomycosis in the second or third trimester of pregnancy are at increased risk of dissemination. Azoles should be avoided during the first trimester of pregnancy because of teratogenicity concerns.

Patient Education

  • Discuss adverse effects of the selected medication(s) and how the patient should respond in the event of rashes, diarrhea, and other complications.
  • Explain the purpose of each medication, and be sure that patients understand the dosage and frequency of administration.
  • Reinforce the need to continue taking the medication indefinitely (potentially for life) to reduce the risk of the OI.
  • OIs can occur despite prophylaxis. Instruct patients to contact their health care provider if they become ill.
  • Counsel patients who are Toxoplasma IgG negative to avoid exposure to Toxoplasma. Specifically, they should avoid eating raw or undercooked meat, especially pork, lamb, game, and venison. Patients should wash hands after handling raw meat and after gardening or contact with soil. Encourage patients not to adopt or handle stray cats, and, if they own cats, to wash hands thoroughly after cleaning litter boxes. (See chapter Preventing Exposure to Opportunistic and Other Infections.)
  • For women of childbearing potential who are taking clarithromycin, emphasize the need for effective contraception to avoid potential teratogenic effects of clarithromycin.
  • Educate patients in Histoplasma- and Coccidioides-endemic areas regarding measures to decrease exposure. (See chapter Preventing Exposure to Opportunistic and Other Infections.)

References