Opportunistic Infection Prophylaxis

July 2006

Chapter Contents

Background

Pneumocystis jiroveci Pneumonia

Disseminated Mycobacterium avium Complex

Toxoplasmosis

Patient Education

References

Background

Prophylaxis against opportunistic infections (OIs) is treatment given to HIV-infected individuals to prevent either a first episode of an OI (primary prophylaxis) or the recurrence of infection (secondary prophylaxis). Prophylaxis is recommended to prevent 3 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 ). In certain situations, prophylaxis against some other OIs may be reasonable; see the OI prevention guidelines of the U.S. Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) (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 or a history of oral thrush. PCP prophylaxis may be indicated in patients with CD4 counts of >200 cells/µL in the presence of a CD4 percentage <14%, other OIs, or fever >100°F that persists for >2 weeks.
• In 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 between 200 and 250 cells/µL if laboratory monitoring will not be possible within 3 months.

Prophylaxis Options: Recommended Regimen

• The recommended regimen is trimethoprim-sulfamethoxazole (TMP-SMX; cotrimoxazole, Bactrim, Septra) 1 double-strength tablet daily. An alternative dosage is TMP-SMX 1 single-strength tablet daily, although the lower dosage may not be as effective. (Note: These regimens also are effective in preventing toxoplasmosis.)
  • Warning: Many patients cannot tolerate sulfa medications. Severe reactions may include persistent neutropenia; rash, including severe erythroderma; and Stevens-Johnson syndrome (bullae and desquamation of the skin). Some patients with milder reactions (eg, rash without fevers or systemic symptoms) may undergo desensitization, but this must be done cautiously and 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:

• Dapsone 100 mg orally daily or 50 mg orally twice daily. (Note: These regimens do not prevent toxoplasmosis.)
• Dapsone 50 mg orally daily + pyrimethamine 50 mg orally once per week + leucovorin 25 mg orally once per week. (Note: This regimen also is effective in reducing the risk of toxoplasmosis.)
• Dapsone 200 mg orally + pyrimethamine 75 mg + leucovorin 25 mg, all once per week. (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.)
• 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 in patients in whom TB is suspected. The availability of treatment facilities offering aerosolized pentamidine may be limited.
• Atovaquone suspension 1,500 mg daily. (Note: This is also effective in reducing the risk of toxoplasmosis.) Atovaquone is more expensive than dapsone. It should be taken with high-fat meals for optimal absorption.
• TMP-SMX 1 double-strength tablet orally 3 times per week (eg, Monday, Wednesday, Friday).

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.
• If PCP prophylaxis is discontinued, the patient's clinical status and CD4 count must be observed closely to determine when to resume prophylaxis.
• 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. Prophylaxis that includes pyrimethamine generally should be deferred until after pregnancy. During the first trimester, aerosolized pentamidine can be used, if the potential teratogenicity of oral agents is a concern.

Disseminated Mycobacterium avium Complex

Background

Disseminated MAC (DMAC) is common in patients with advanced HIV disease and 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 ). Review the current drug regimen for medications that may interact with DMAC prophylaxis.

Prophylaxis Options: Recommended Regimens

• Azithromycin 1,200 mg weekly or clarithromycin 500 mg orally twice a day. (Note: Clarithromycin is not recommended during pregnancy, and it can have significant interactions with efavirenz and other drugs; see chapter Drug-Drug Interactions with HIV-Related Medications .) Note that if breakthrough DMAC occurs, it may be macrolide resistant.

Prophylaxis Options: Alternative Regimens

• Rifabutin 300 mg daily, or azithromycin 1,200 mg daily + rifabutin 300 mg daily. (Note: Rifabutin has significant interactions with many drugs; certain nonnucleoside reverse transcriptase inhibitors and protease inhibitors should be avoided or dose adjusted if used with rifabutin. 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 .

Discontinuing Primary Prophylaxis

Primary prophylaxis for DMAC 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 <50-100 cells/µL.

Secondary prophylaxis can be discontinued in patients who received at least 12 months of treatment for DMAC, are asymptomatic, and have sustained (for at least 6 months) CD4 counts of >100 cells/µL during ART.

Prophylaxis during Pregnancy

Azithromycin is the prophylactic drug of choice during pregnancy, although some providers withhold it during the first trimester. Clarithromycin is teratogenic in animals.

Toxoplasmosis

Background

Toxoplasmic encephalitis (TE) is 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 USPHS/IDSA guidelines recommend that all HIV-infected patients be tested for toxoplasmosis immunoglobulin G (IgG) antibody soon after the diagnosis of HIV infection. Toxoplasmosis 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 toxoplasmosis IgG when CD4 counts fall to <100 cells/µL to determine whether they have seroconverted and are therefore at risk for 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.

Prophylaxis Options: Recommended Regimen

• TMP-SMX 1 double-strength tablet daily. (Note: This option is also effective in preventing PCP.)

Prophylaxis Options: Alternative Regimens

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

• TMP-SMX, 1 single-strength tablet daily.
• Dapsone 50 mg daily + pyrimethamine 50 mg weekly + folinic acid 25 mg weekly.
• Dapsone 200 mg weekly + pyrimethamine 75 mg weekly + folinic acid 25 mg orally 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 orally daily, with or without pyrimethamine 25 mg daily + folinic acid 10 mg daily; however, 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 <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 during ART.

Prophylaxis during Pregnancy

TMP-SMX may be used as primary prophylaxis during pregnancy. Prophylaxis that includes pyrimethamine generally should be deferred until after pregnancy, although pyrimethamine may be used with caution to treat active toxoplasmosis during pregnancy in sulfa-allergic patients.

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 the medication indefinitely (potentially for life) to reduce the risk of the OI.
• OIs can occur despite prophylaxis. Instruct patients to call their health care providers 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.

References

• Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association/Infectious Diseases Society of America. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents . MMWR Recomm Rep. 2004 Dec 17; 53(RR15);1-112. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=14.
• El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both . N Engl J Med. 1998 Dec 24;339(26):1889-95.
• Hardy WD, Feinberg J, Finkelstein DM, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome . N Engl J Med. 1992 Dec 24;327(26):1842-8.
• Masur H. Prevention and treatment of pneumocystis pneumonia . N Engl J Med. 1992 Dec 24;327(26):1853-60.
• Sande MA, Eliopoulos GM, Moellering RC, et al. The Sanford Guide to HIV/AIDS Therapy, 14th ed. Hyde Park, VT: Antimicrobial Therapy, Inc.; 2005.
• U.S. Public Health Service, Infectious Diseases Society of America. Guidelines for preventing opportunistic infections among HIV-infected persons--2002 . MMWR Recomm Rep. 2002 Jun 14;51(RR08);1-46. Available online at aidsinfo.nih.gov/Guidelines/.