Do We Need Prophylaxis for Pneumocystis jirovecii Pneumonia in Virologically Suppressed Patients?

US Department of Health and Human Services guidelines recommend that primary Pneumocystis prophylaxis be discontinued in patients who have responded to antiretroviral therapy (ART) with an increase in CD4+ cell counts to >200 cells/mm³ for ≥ 3 months. Despite sustained virologic response, approximately 15% to 20% of patients with lower nadir CD4+ cell counts (<200 cells/mm³) at ART initiation will fail to have the desired immunologic recovery. These so-called “immunologic nonresponders” have a higher risk of mortality and morbidity compared with their counterparts with immunologic recovery. Therefore, healthcare professionals’ current approach to immunologic nonresponse should focus on: (1) prevention (early initiation of ART before significant CD4+ cell decline), (2) ruling out alternative causes of lymphopenia (drug toxicities, viral coinfections, malignancies), and (3) mitigation of downstream consequences of immunosuppression.

Should Pneumocystis jirovecii Pneumonia (PJP) Prophylaxis Be Discontinued in the Context of Sustained Virologic Response With Lower CD4+ Cell Counts?
But what about PJP prophylaxis in patients who have virologic response but lower CD4+ cell counts? In addition to addressing the 3 items above, should PJP prophylaxis be discontinued? This question merits discussion, because the first-line prophylactic drug trimethoprim-sulfamethoxazole (TMP-SMX) is associated with a common adverse event (up to 57% in the context of PJP therapy), and there are little data to support this recommendation.

Fortunately, the emerging consensus—based on large observational studies and a small randomized, controlled trial—is that primary and secondary prophylaxis against PJP can be safely stopped in patients with CD4+ cell counts from 101-200 cells/mm³ who were virologically suppressed on ART for ≥3-6 months. In the COHERE study, prophylaxis significantly reduced the incidence of PJP in virologically suppressed patients (plasma HIV-1 RNA <50 to 400 copies/mL) with CD4+ cell counts <100 cells/mm³, but not in those with CD4+ cell counts from 100-200 cells/mm³. There were no cases in the latter group when prophylaxis was discontinued.

What Is the Appropriate Dose of TMP-SMX for PJP Prophylaxis?
The recommended dose of TMP-SMX for PJP prophylaxis is 1 double-strength tablet (160 mg TMP and 800 mg SMX) daily, but 1 single-strength tablet daily or even 1 double-strength tablet 3 times weekly is an effective regimen and may be better tolerated. However, the evidence behind these dosing recommendations is weak, stemming from studies conducted almost 3 decades ago, prior to the availability of highly active ART.

Even lower doses might confer protection with potentially lower toxicity, as TMP-SMX adverse events are dose related. A recent meta-analysis has shown that a reduced dose of TMP-SMX (≤15 mg/kg/day of trimethoprim) has clinical efficacy comparable with the standard dose for the treatment of PJP, with 18% fewer severe adverse events. There has not been similar reassessment of TMP-SMX doses for PJP prophylaxis.

Alternatives to TMP-SMX in patients who cannot tolerate it include dapsone, dapsone plus pyrimethamine plus leucovorin, atovaquone, and aerosolized pentamidine with the Respirgard II nebulizer. For patients testing seropositive for Toxoplasma gondii, aerosolized pentamidine or dapsone alone should not be used, as they are ineffective prophylaxis for toxoplasmosis.

In conclusion, there appears to be a great need for well-designed randomized, controlled trials to address: (1) the need for PJP prophylaxis in virologically suppressed patients in the current ART era and (2) the most effective regimen for PJP prophylaxis with the least toxicity.

Your Thoughts?
How many of your patients currently receiving PJP prophylaxis have switched from the guideline-recommended regimen to an alternative regimen due to adverse events? Join the discussion by posting a comment.