What is the recommended prophylaxis for Pneumocystis jirovecii pneumonia (PJP) in an HIV-positive patient with a CD4 count below 200 cells/mm^3?

PJP Prophylaxis in HIV: CD4 Count Thresholds

Start PJP prophylaxis when CD4 count falls below 200 cells/mm³, using trimethoprim-sulfamethoxazole (TMP-SMX) one double-strength tablet daily as first-line therapy. 1, 2

Primary Prophylaxis Initiation Criteria

Absolute indications for starting prophylaxis:

• CD4 count <200 cells/mm³ (strongest evidence, AI rating) 1, 2
• History of oropharyngeal candidiasis, regardless of CD4 count 1, 3, 2
• CD4 percentage <14% (even if absolute count >200 cells/mm³) 1, 4

Consider prophylaxis in these situations:

• CD4 count 200-250 cells/mm³ when monitoring every 3 months is not feasible 1
• Unexplained fever >100°F for ≥2 weeks 3
• Rapidly declining CD4 counts approaching 200 cells/mm³ 1

First-Line Prophylactic Regimen

TMP-SMX is the preferred agent with proven 91% reduction in PJP occurrence and 83% reduction in PJP-related mortality: 2

Dosing options (in order of preference):

• One double-strength tablet (800mg SMX/160mg TMP) daily (preferred) 1, 2
• One single-strength tablet daily (better tolerated, equally effective) 1
• One double-strength tablet three times weekly (also effective) 1

Critical advantage: TMP-SMX provides cross-protection against toxoplasmosis, nocardiosis, listeriosis, and common bacterial respiratory infections 1, 2

Alternative Regimens (When TMP-SMX Cannot Be Tolerated)

Ranked by evidence quality:

1. Dapsone 100mg PO daily - requires G6PD testing before initiation 1, 2
2. Dapsone 50mg daily PLUS pyrimethamine 50mg weekly PLUS leucovorin 25mg weekly - provides toxoplasmosis coverage for seropositive patients 1
3. Atovaquone 1,500mg PO daily - equivalent efficacy to dapsone but substantially more expensive 1, 2, 5
4. Aerosolized pentamidine 300mg monthly via Respirgard II nebulizer - less effective, reserve for patients intolerant to oral agents 1, 2

Important caveat: For patients seropositive for Toxoplasma gondii who cannot tolerate TMP-SMX, use dapsone plus pyrimethamine or atovaquone with/without pyrimethamine to maintain dual coverage 1

Managing TMP-SMX Intolerance

If non-life-threatening adverse reaction occurs:

• Continue TMP-SMX if clinically feasible 1
• If discontinued, strongly consider reintroduction after reaction resolves 1
• Use gradual dose escalation (desensitization) - up to 70% of patients can tolerate reinstitution 1
• Alternative: reduce dose or frequency temporarily 1

Discontinuing Primary Prophylaxis

Safe to discontinue when ALL of the following are met:

• CD4 count rises to >200 cells/mm³ for ≥3 months 1, 2
• Patient on effective antiretroviral therapy (ART) 1, 2
• Sustained viral suppression (HIV RNA below detection limits) 1, 2
• Median CD4 at safe discontinuation in studies was >300 cells/mm³ 1, 2

Restart prophylaxis immediately if:

• CD4 count decreases to <200 cells/mm³ 1

Secondary Prophylaxis (After PCP Episode)

Lifelong secondary prophylaxis is required for patients with prior PCP, using the same regimens as primary prophylaxis. 1, 2

Can discontinue secondary prophylaxis when:

• CD4 count increases from <200 to >200 cells/mm³ for ≥3 months on HAART 1
• Sustained viral suppression documented 1
• Median CD4 at discontinuation in studies was >300 cells/mm³ 1

Exception - never discontinue if:

• Original PCP episode occurred at CD4 >200 cells/mm³ - continue prophylaxis for life regardless of immune reconstitution 1

Restart secondary prophylaxis if:

• CD4 decreases to <200 cells/mm³ 1
• PCP recurred at CD4 >200 cells/mm³ 1

Emerging Evidence: Lower CD4 Thresholds

Recent high-quality research suggests prophylaxis may be safely withheld in specific circumstances:

For patients with CD4 100-200 cells/mm³ who have:

• Suppressed viral load (<400 copies/mL) on ART 6, 7, 8
• PJP incidence off prophylaxis: 3.9 per 1000 person-years (not significantly different from those on prophylaxis at 1.9 per 1000 person-years) 6
• Zero PJP cases occurred in patients who discontinued prophylaxis after starting ART with CD4 101-200 cells/mm³ 7

However, current US and European guidelines have not yet universally adopted CD4 >100 cells/mm³ as the discontinuation threshold, so the standard 200 cells/mm³ threshold remains the safest recommendation for routine practice. 2

Critical Monitoring Requirements

Measure both CD4 count AND CD4 percentage at baseline and every 3-6 months: 2, 4

• 13% of patients have discordance between absolute count and percentage 4
• Patients with CD4 count >200 but CD4% <14 are significantly undertreated (only 29% receive prophylaxis vs 86% when count <200) 4

Complete blood count with differential monthly when on TMP-SMX to monitor for cytopenias 2

Screen for active pulmonary disease (PCP, TB, histoplasmosis) before initiating prophylaxis - these require treatment, not prophylaxis 2

Timing with ART Initiation

Start ART as soon as possible after HIV diagnosis, ideally immediately or within 2 weeks, regardless of CD4 count 2, 9

Initiate PJP prophylaxis immediately if CD4 <200 cells/mm³, even before ART is started or while awaiting CD4 results if clinical suspicion is high 3, 2

For patients presenting with pneumonia and CD4 <200 cells/mm³, add TMP-SMX for PCP coverage to empiric bacterial pneumonia treatment 3

Common Pitfalls to Avoid

• Never rely solely on CD4 percentage without checking absolute count - 13% of patients have discordance that affects prophylaxis decisions 4
• Never withhold prophylaxis in patients with oropharyngeal candidiasis, even if CD4 >200 cells/mm³ 1, 3
• Never forget G6PD testing before starting dapsone - risk of severe hemolysis 2
• Never use aerosolized pentamidine with nebulizers other than Respirgard II - insufficient efficacy data 1
• Never continue prophylaxis indefinitely without reassessing - reduces pill burden, toxicity, drug interactions, and cost when safely discontinued 1
• Failure to prescribe prophylaxis when indicated is associated with 10.8-fold increased mortality risk, even in the ART era 10