When should cotrimoxazole (trimethoprim‑sulfamethoxazole) prophylaxis be started in an HIV‑positive individual (CD4 ≤200 cells/µL, pregnancy, infant of an HIV‑positive mother, or risk for Pneumocystis jirovecii pneumonia, toxoplasmosis, severe bacterial infection, or malaria), and what are the recommended dosing, duration, monitoring, contraindications, and alternative agents if intolerant?

Cotrimoxazole Prophylaxis in HIV

When to Start Prophylaxis

All HIV-positive adults and adolescents (including pregnant women) should start cotrimoxazole prophylaxis when their CD4 count falls below 200 cells/µL. 1

Primary Indications for Initiation

• CD4 count <200 cells/µL is the primary threshold for starting prophylaxis, regardless of symptoms or antiretroviral therapy (ART) status. 1
• Patients with a history of oropharyngeal candidiasis should receive prophylaxis even if CD4 count is above 200 cells/µL. 1
• Consider starting prophylaxis when CD4 percentage is <14% or when the patient has had any AIDS-defining illness. 1
• In settings where CD4 monitoring every 3 months is not feasible, consider initiating prophylaxis at CD4 counts between 200-250 cells/µL to avoid missing the threshold. 1

Special Populations

• Infants born to HIV-positive mothers should start cotrimoxazole at 4-6 weeks of age and continue through the first year of life, regardless of HIV infection status. 1
• HIV-infected children should continue prophylaxis based on age-specific CD4 thresholds after the first year. 1
• Pregnant women with HIV should receive prophylaxis using the same CD4 criteria as other adults; TMP-SMZ is the preferred agent. 1
• Providers may choose to withhold prophylaxis during the first trimester due to theoretical teratogenicity concerns, substituting aerosolized pentamidine if needed, though this is a weaker recommendation. 1

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Recommended Dosing Regimens

The preferred regimen is trimethoprim-sulfamethoxazole (TMP-SMZ) double-strength tablet (160 mg TMP/800 mg SMZ) once daily. 1, 2

Alternative Dosing Schedules

• One single-strength tablet daily is also effective and may be better tolerated than double-strength. 1
• One double-strength tablet three times weekly (e.g., Monday, Wednesday, Friday) is an acceptable alternative regimen. 1, 2
• Daily double-strength dosing provides the best cross-protection against toxoplasmosis and common respiratory bacterial infections, which is particularly important at very low CD4 counts. 1, 2

Renal Dose Adjustment

• For creatinine clearance 15-30 mL/min, reduce the dose to 50% of the usual regimen. 3
• TMP-SMZ is not recommended when creatinine clearance is below 15 mL/min. 3
• Note that trimethoprim blocks tubular secretion of creatinine, causing falsely elevated serum creatinine without actual decline in kidney function; use 24-hour urine collection for accurate assessment if needed. 2

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Duration and Discontinuation Criteria

Prophylaxis should continue lifelong unless immune reconstitution occurs with effective ART. 1, 2

Safe Discontinuation

• Prophylaxis can be discontinued when CD4 count rises above 200 cells/µL and remains elevated for at least 3-6 consecutive months on ART. 1, 2
• Many experts also require sustained viral suppression below detection limits for 3-6 months before discontinuing prophylaxis. 1
• The median CD4 count at discontinuation in clinical studies was >300 cells/µL, suggesting this is a safer threshold than 200 cells/µL. 1

Restarting Prophylaxis

• Restart prophylaxis immediately if CD4 count falls below 200 cells/µL after previous discontinuation. 1, 2
• Some experts recommend restarting at CD4 counts between 100-200 cells/µL depending on clinical circumstances. 1

Secondary Prophylaxis (After PCP Episode)

• Patients with a history of PCP require lifelong secondary prophylaxis using the same regimens, regardless of CD4 recovery. 1
• Insufficient data exist to recommend discontinuing secondary prophylaxis even with immune reconstitution on ART. 1

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Managing Adverse Reactions

Up to 70% of patients who develop non-life-threatening reactions to TMP-SMZ can tolerate rechallenge using desensitization protocols. 1, 2

Approach to Mild-to-Moderate Reactions

• For mild rash, low-grade fever, or mild cytopenias, continue TMP-SMZ if clinically feasible rather than switching to less effective alternatives. 1, 2
• After resolution of the adverse event, strongly consider reintroducing TMP-SMZ using gradual dose escalation (desensitization). 1
• Alternative approach: restart at reduced dose or reduced frequency (e.g., single-strength daily or double-strength three times weekly) before abandoning the drug. 1

When to Permanently Discontinue

• Life-threatening reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, severe bone marrow suppression, anaphylaxis) require permanent discontinuation. 1

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Alternative Agents for TMP-SMZ Intolerance

If TMP-SMZ cannot be tolerated, dapsone 100 mg daily is the first-line alternative. 1, 4

Alternative Regimens in Order of Preference

• Dapsone 50 mg daily + pyrimethamine 50 mg weekly + leucovorin 25 mg weekly provides dual protection against PCP and toxoplasmosis for patients who are Toxoplasma-seropositive. 1, 2
• Aerosolized pentamidine 300 mg monthly via Respirgard II nebulizer is effective but does not protect against toxoplasmosis or bacterial infections. 1, 4
• Atovaquone 1500 mg daily is as effective as dapsone or aerosolized pentamidine but is substantially more expensive. 1, 4

Critical Contraindications

• Dapsone is absolutely contraindicated in patients with G6PD deficiency due to risk of severe hemolysis; check G6PD status before prescribing. 4
• Primaquine is also contraindicated in G6PD deficiency. 4
• For G6PD-deficient patients who cannot tolerate TMP-SMZ, atovaquone is the safest alternative. 4

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Monitoring Requirements

• Monitor complete blood count monthly in patients on chronic TMP-SMZ, as hematologic toxicity increases with duration of therapy. 2
• Monitor renal function, electrolytes (especially potassium), and liver enzymes regularly. 2, 3
• Elderly patients and those on ACE inhibitors or diuretics are at increased risk for hyperkalemia; close potassium monitoring is essential. 3
• Monitor digoxin levels in patients taking both digoxin and TMP-SMZ, especially in elderly patients. 3

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Additional Benefits Beyond PCP Prevention

Daily TMP-SMZ provides important cross-protection against multiple opportunistic infections. 1, 5

Proven Additional Benefits

• Reduces toxoplasmosis risk, particularly at double-strength daily dosing. 1
• Reduces common respiratory bacterial infections. 1
• Reduces malaria incidence by 75% in malaria-endemic areas of Africa. 5
• Reduces diarrheal illness by 39%. 5
• Reduces hospital admissions by 58% when continued after immune reconstitution on ART. 5
• Reduces early mortality by 58% in adults starting ART. 6

Pregnant Women and Infants

• Cotrimoxazole prophylaxis in pregnant women with low CD4 counts reduces preterm delivery and neonatal mortality. 7
• Cotrimoxazole is non-inferior to intermittent preventive treatment for malaria (IPTp) in preventing infant mortality, low birthweight, and placental malaria in Africa. 5
• Pregnant women with HIV in Africa should use cotrimoxazole rather than IPTp for malaria prevention. 5

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Key Clinical Pitfalls to Avoid

• Do not delay initiation when CD4 is <200 cells/µL; the risk of life-threatening opportunistic infections is extremely high at these levels. 2
• Do not abandon TMP-SMZ for minor adverse reactions without attempting desensitization or dose modification first. 1, 2
• Do not prescribe dapsone or primaquine without first checking G6PD status. 4
• Do not discontinue prophylaxis based solely on viral suppression; CD4 count must be >200 cells/µL for at least 3-6 months. 1
• Do not use TMP-SMZ in neonates under 2 months of age due to bilirubin displacement concerns. 3
• In settings with high burden of infectious diseases (malaria, bacterial infections), consider continuing cotrimoxazole prophylaxis indefinitely regardless of CD4 recovery on ART. 5