What are the primary prophylaxis, secondary prophylaxis, and treatment strategies for opportunistic infections in HIV-positive patients based on CD4 (Cluster of Differentiation 4) count, according to the National AIDS Control Organization (NACO) 2021 guidelines?

Opportunistic Infection Prophylaxis in HIV Based on CD4 Count

Start primary prophylaxis for Pneumocystis jirovecii pneumonia (PCP) with trimethoprim-sulfamethoxazole (TMP-SMX) one double-strength tablet daily when CD4 count falls below 200 cells/μL, initiate Toxoplasma prophylaxis at CD4 <100 cells/μL in IgG-positive patients, and begin Mycobacterium avium complex (MAC) prophylaxis with azithromycin when CD4 drops below 50 cells/μL. 1, 2

Primary Prophylaxis by CD4 Threshold

CD4 <200 cells/μL: PCP Prophylaxis

• Preferred regimen: TMP-SMX 800mg/160mg (double-strength) one tablet orally daily 1, 2
• Alternative dosing: TMP-SMX one double-strength tablet three times weekly is also highly effective and may be better tolerated 1, 2
• Second-line options: Dapsone 100 mg orally daily (test for G6PD deficiency first) 1, 2
• Third-line: Aerosolized pentamidine via Respirgard II nebulizer 1
• Additional indications: Consider prophylaxis even with CD4 >200 cells/μL if CD4 percentage <14%, history of AIDS-defining illness, or oropharyngeal candidiasis 1

CD4 <100 cells/μL: Toxoplasma Prophylaxis

• Indication: Only for patients with positive Toxoplasma IgG antibody 1, 2
• Preferred regimen: TMP-SMX double-strength daily (provides dual protection against PCP and Toxoplasma) 1
• Alternative: Dapsone 50 mg daily plus pyrimethamine 50 mg weekly plus leucovorin 25 mg weekly 1
• Note: Patients already on TMP-SMX for PCP prophylaxis require no additional medication 1

CD4 <50 cells/μL: MAC Prophylaxis

• Preferred regimen: Azithromycin 1200 mg orally once weekly 1, 2
• Alternative: Clarithromycin 500 mg orally twice daily 1
• Second alternative: Rifabutin 300 mg orally daily (caution with drug interactions with antiretrovirals) 1

Additional Prophylaxis Considerations

• Cryptococcus (CD4 <50 cells/μL): Fluconazole 100-200 mg daily, though this remains optional 1
• Histoplasma (CD4 <100 cells/μL in endemic areas): Itraconazole capsule 200 mg daily 1
• CMV (CD4 <50 cells/μL with CMV antibody positive): Oral ganciclovir 1 gram three times daily, though routine primary prophylaxis is not universally recommended 1

Secondary Prophylaxis (After Documented Infection)

PCP Secondary Prophylaxis

• Regimen: Same as primary prophylaxis - TMP-SMX double-strength daily 1
• Duration: Lifelong unless immune reconstitution occurs 1

Toxoplasmosis Secondary Prophylaxis

• Preferred: Sulfadiazine 2-4 grams daily (divided doses) plus pyrimethamine 25-50 mg daily plus leucovorin 10-25 mg daily 1
• Alternative: Clindamycin 600 mg every 8 hours plus pyrimethamine plus leucovorin 1
• Duration: Lifelong unless immune reconstitution 1

MAC Secondary Prophylaxis

• Regimen: Clarithromycin 500 mg twice daily plus ethambutol 15 mg/kg daily, with or without rifabutin 1
• Alternative: Azithromycin 500 mg daily plus ethambutol 1
• Duration: At least 12 months of therapy required before considering discontinuation 1

Cryptococcal Meningitis Secondary Prophylaxis

• Regimen: Fluconazole 200 mg daily 1
• Duration: Lifelong unless immune reconstitution 1

CMV Retinitis Secondary Prophylaxis

• Regimen: Ganciclovir 5 mg/kg IV daily or foscarnet 90-120 mg/kg IV daily 1
• Alternative: Ganciclovir sustained-release implant every 6-9 months plus oral ganciclovir 1

Treatment of Active Opportunistic Infections

PCP Treatment

• Regimen: TMP-SMX 15-20 mg/kg/day (based on TMP component) divided three times daily for 21 days 2
• Adjunctive corticosteroids: Add prednisone for moderate-severe disease (PaO2 <70 mmHg or A-a gradient >35 mmHg) 2
• Alternative: Pentamidine IV, atovaquone, or clindamycin-primaquine for TMP-SMX intolerance 1

Candidiasis Treatment

• Mild oral/esophageal: Nystatin suspension 2
• Moderate-severe: Fluconazole 200-400 mg daily (avoid during pregnancy) 2
• Refractory cases: Itraconazole solution or voriconazole 1

Toxoplasmosis Treatment

• Acute therapy: Pyrimethamine 200 mg loading dose, then 50-75 mg daily plus sulfadiazine 1-1.5 grams four times daily plus leucovorin 10-25 mg daily for at least 6 weeks 1
• Alternative: Pyrimethamine plus leucovorin plus clindamycin 600 mg IV/PO every 6 hours 1

Discontinuing Prophylaxis (Immune Reconstitution)

PCP Prophylaxis Discontinuation

• Criteria: CD4 count >200 cells/μL for ≥3 months on ART with sustained virologic suppression 1, 2
• Restart if: CD4 count drops below 200 cells/μL 1

Toxoplasma Prophylaxis Discontinuation

• Criteria: CD4 count >200 cells/μL for ≥3 months on ART 1, 2
• Restart if: CD4 count drops below 100-200 cells/μL 1

MAC Prophylaxis Discontinuation

• Criteria: CD4 count >100 cells/μL for ≥3 months on ART with sustained virologic suppression 1, 2
• Restart if: CD4 count drops below 50-100 cells/μL 1

Secondary Prophylaxis Discontinuation

• Toxoplasmosis: Can discontinue when CD4 >200 cells/μL sustained for ≥6 months, completed initial therapy, and asymptomatic 1
• MAC: Can discontinue when CD4 >100 cells/μL sustained for ≥6 months, completed 12 months of therapy, and asymptomatic 1
• Cryptococcosis: Can discontinue when CD4 >100-200 cells/μL sustained for ≥6 months, completed initial therapy, and asymptomatic 1
• CMV retinitis: Can discontinue when CD4 >100-150 cells/μL sustained for ≥6 months with no active disease and regular ophthalmologic examination 1

Critical Pitfalls to Avoid

• Do not base prophylaxis decisions on current CD4 count alone if patient previously had lower counts: Most experts recommend initiating or continuing prophylaxis based on the lowest CD4 count ever recorded, not just the most recent value after ART initiation 1
• Do not discontinue prophylaxis prematurely: Ensure sustained CD4 recovery for the full specified duration (typically 3-6 months) before stopping 1, 2
• Monitor for drug interactions: Rifabutin has substantial interactions with protease inhibitors and NNRTIs; rifampin interactions are even more severe - consult HIV pharmacist 1
• Avoid zidovudine with TMP-SMX: Increased risk of myelosuppression 1
• Test for G6PD deficiency before dapsone: Hemolysis can occur in deficient individuals 1
• Ensure adequate hydration with TMP-SMX: Prevent crystalluria and stone formation 3
• AIDS patients may not tolerate TMP-SMX: Higher incidence of rash, fever, leukopenia in AIDS patients; monitor closely and consider alternatives early 3
• Monitor potassium with high-dose TMP-SMX: Hyperkalemia risk, especially in PCP treatment doses 3
• Do not use leucovorin with TMP-SMX for PCP treatment: Avoid coadministration during active PCP therapy 1

Special Populations

Pregnancy

• Continue PCP prophylaxis: TMP-SMX can be used, though some avoid in first trimester 1
• Avoid fluconazole: Teratogenic risk; use alternative antifungals 2

Pediatric Dosing

• PCP prophylaxis: TMP-SMX 150/750 mg/m² in 2 divided doses daily 1
• MAC prophylaxis: Clarithromycin 7.5 mg/kg (max 500 mg) twice daily or azithromycin 5 mg/kg (max 250 mg) daily 1

Renal Impairment

• Adjust TMP-SMX dose: CrCl 15-30 mL/min: use half the usual dose; CrCl <15 mL/min: not recommended 3