Clinical Guide > Maintenance and Prevention > OI Prophylaxis

# Opportunistic Infection Prophylaxis

January 2011

### Chapter Contents

      - Background
      - Patient Education
      - ReferencesHRSA HAB Core Clinical Performance MeasuresBackground
Prophylaxis against 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 infection (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*). 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. Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) (reference below) for additional information.
*Pneumocystis jiroveci* PneumoniaBackground
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 for patients with CD4 counts of >200 cells/µL in the presence of a CD4 percentage <14%, or a history of an AIDS-defining illness.
- 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) one double-strength tablet PO once daily (Note: This regimen also is effective in preventing toxoplasmosis.)
- TMP-SMX one single-strength tablet PO once daily (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 one double-strength tablet TIW (e.g., Monday, Wednesday, and Friday) (Note: This regimen also is likely to be effective in preventing toxoplasmosis.)
- Dapsone 100 mg PO once daily or 50 mg PO BID (Note: These regimens do not prevent toxoplasmosis.)
- Dapsone 50 mg PO once daily + 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.)
- 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 suspension 1,500 mg once daily (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 suspension 1,500 mg + pyrimethamine 25 mg + folinic acid 10 mg all taken PO once daily (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. 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* ComplexBackground
*Mycobacterium avium* complex (MAC) is common among patients with advanced HIV disease and it 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*). 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 once daily (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*.
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
ToxoplasmosisBackground
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 USPHS/IDSA 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 when 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.
Prophylaxis Options: Recommended Regimens- TMP-SMX one double-strength tablet once 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, one double-strength tablet PO TIW
- TMP-SMX, one single-strength tablet PO once daily
- Dapsone 50 mg PO once daily + 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 once daily, with or without pyrimethamine 25 mg PO once daily + folinic acid 10 mg PO once 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 <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 daily) for pregnant women receiving TMP-SMX, because TMP-SMX may worsen folate deficiency. Pyrimethamine has been associated with birth defects in animal studies, but limited data in human studies have not shown an increased risk. Secondary prophylaxis generally should be provided using the same guidelines as for nonpregnant women.
HistoplasmosisBackground
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 once daily (Note: Itraconazole has significant interactions with many drugs, including nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), 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 ≥150 cells/µL for at least 6 months on ART, and have serum *Histoplasma* antigen <2 units.
Prophylaxis During Pregnancy
Azoles should not be used during the first trimester of pregnancy because of teratogenicity concerns.
CoccidiomycosisBackground
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
HIV-infected persons from *Coccidioides*-endemic areas with positive IgM or IgG serologies are at increased risk of developing active infection, especially if their CD4 counts are ≤250 cells/µL. Many experts would recommend primary prophylaxis for such patients. Annual monitoring for seroconversion of HIV-infected patients in endemic areas is prudent. Patients in endemic areas should be educated to avoid exposure.
Prophylaxis Options: Recommended Regimens- Fluconazole 400 mg PO once daily
- Itraconazole 200 mg PO BID

(Note: Itraconazole has significant interactions with many drugs, including NNRTIs, PIs, and maraviroc. Dosage adjustments may be required, and some combinations may be contraindicated; consult with a pharmacist or other specialist.)
Secondary Prophylaxis
Patients who have completed initial treatment for coccidiomycosis should be considered for lifelong chronic maintenance therapy.
Discontinuing Prophylaxis
Primary prophylaxis can be discontinued once CD4 counts are ≥250 cells/µL for at least 6 months, but should be restarted if the CD4 count drops to <250 cells/µL.

Suppressive therapy should be continued lifelong for patients with a history of diffuse pulmonary, disseminated, or meningeal disease, as these patients are at high risk of relapse. 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 >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 not be used 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- Centers for Disease Control and Prevention.  Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America . April 10, 2009.
- Centers for Disease Control and Prevention.  Coccidiomycosis . In:  CDC Health Information for International Travel 2010 . Atlanta: U.S. Department of Health and Human Services, Public Health Service, 2009.
- Centers for Disease Control and Prevention.  Histoplasmosis . In:  CDC Health Information for International Travel 2010 . Atlanta: U.S. Department of Health and Human Services, Public Health Service, 2009.
**HRSA HAB Core Clinical Performance MeasuresPercentage of clients with HIV infection and a CD4 count of <200 cells/µL who were prescribed ***Pneumocystis jiroveci* pneumonia prophylaxis** (Group 1) Percentage of clients with HIV infection and a CD4 count of <50 cells/µL who were prescribed ***Mycobacterium avium* complex prophylaxis** within the measurement year (Group 3)**