Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Intermittent trimethoprim-sulfamethoxazole and dapsone-pyrimethamine reduced P. carinii pneumonia in HIV infection

ACP J Club. 1995 Sept-Oct;123:41. doi:10.7326/ACPJC-1995-123-2-041


Source Citation

Podzamczer D, Salazar A, Jiménez J, et al. Intermittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of pneumocystis pneumonia and toxoplasmosis in patients infected with HIV. Ann Intern Med. 1995 May 15;122:755-61.


Abstract

Objective

To evaluate the effectiveness and safety of 2 oral, intermittent drug therapies for the prevention of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis in patients with the human immunodeficiency virus (HIV) infection.

Design

Randomized controlled trial with median 14-month follow-up.

Setting

University teaching hospital in Barcelona, Spain.

Patients

230 patients (mean age 33 y, 82% men) with HIV infection and a CD4+ cell count < 200 × 106/L. Patients were excluded if they had a history of PCP or toxoplasmosis; had a history of allergy to sulfonamides or sulfones; were currently receiving other drugs known to have anti-PCP or antitoxoplasma activity; or had hemoglobin levels < 90 g/L, neutrophil levels < 1.0 × 109/L, alanine aminotransferase levels > 5 times normal, and creatinine levels > twice normal. 200 patients (87%) completed the study.

Intervention

104 patients were assigned to receive trimethoprim, 160 mg, plus sulfamethoxazole, 800 mg, twice a day on Mondays, Wednesdays, and Fridays (TMP-SMX). 96 patients were assigned to receive dapsone, 100 mg, plus pyrimethamine, 50 mg, twice weekly on Tuesdays and Fridays.

Main outcome measures

PCP, toxoplasmosis, mortality, and adverse effects.

Main results

Analysis was by intention to treat. None of the patients receiving TMP-SMX developed PCP during follow-up compared with 6 patients (6.3%) receiving dapsone-pyrimethamine (P < 0.001) (Table). 5 of the 6 patients who developed PCP had voluntarily stopped taking drug > 2 months before the episode and had received no prophylaxis during that 2-month period. 1 episode of toxoplasmosis occurred in the TMP-SMX group and 2 occurred in the dapsone-pyrimethamine group (P = 0.65). 15 patients receiving TMP-SMX and 14 patients receiving dapsone-pyrimethamine died (P = 0.85) (Table). 19 patients discontinued therapy because of adverse effects: 10 were receiving TMP-SMX and 9 were receiving dapsone-pyrimethamine (P = 0.95).

Conclusions

The effectiveness of intermittent therapy with trimethoprim-sulfamethoxazole was similar to that of intermittent therapy with dapsone-pyrimethamine in preventing Pneumocystis carinii pneumonia and toxoplasmosis in patients with the human immunodeficiency virus infection who were receiving their drug treatment. Both treatments were well tolerated.

Source of funding: In part, Fondo de Investigación de la Seguridad Social.

For article reprint: Not available.


Table. Intermittent trimethoprim-sulfamethoxazole vs intermittent dapsone-pyrimethamine in patients with HIV infection*

Outcomes at median 14 mo Trimethoprim-sulfamethoxazole Dapsone-pyrimethamine RRR (95% CI) NNT (CI)
Development of pneumocystis pneumonia 0% 6.3% 100% (42 to 100) 16 (8 to 39)
Death 14.4% 14.6% 1.1% (-92 to 49) Not significant

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

Trimethoprim-sulfamethoxazole, dapsone, and aerosolized pentamidine reduced P. carinii pneumonia in advanced HIV infection

In the management of patients with HIV infection, providing optimal prophylaxis against PCP in patients at high risk continues to be of the utmost importance (1). Even with the aggressive approach to prophylaxis used in the study by Bozzette and colleagues, the overall cumulative 3-year risk for breakthrough was 18% (data provided by author).

In these 2 well-designed, long-term, open-label randomized clinical trials of PCP prophylaxis, intention-to-treat analyses of the episodes of breakthrough PCP do not show that any one treatment strategy is best. This type of analysis, however, does not do justice to the superior efficacy of TMP-SMX. In the study by Bozzette and colleagues, it was rare for a patient to have breakthrough PCP while still receiving even a reduced dose of TMP-SMX. If the analysis is restricted to the actual prophylaxis received when breakthrough PCP occurs, any systemic prophylaxis is superior to aerosolized pentamidine. A trend exists toward TMP-SMX being more efficacious than dapsone. Additional analyses suggest that low-dose TMP-SMX is probably as good as high-dose TMP-SMX, whereas high-dose dapsone seems better than low-dose dapsone. For compliance and tolerability, however, these rankings are reversed. Although it was unusual for patients receiving aerosolized pentamidine to discontinue this therapy because of adverse events, only one quarter of the patients receiving a systemic regimen could maintain the initial dosage throughout the trial.

In the smaller, shorter study by Podzamczer and colleagues, none of the patients who were assigned to intermittent TMP-SMX had PCP. 6 persons receiving dapsone plus pyrimethamine had PCP using the intention-to-treat analysis; however, all but 1 episode occurred in noncompliant patients.

Both of these studies assessed the efficacy of the regimens for toxoplasmosis prophylaxis. Event rates were low in both studies, even though 65% of the patients in the Podzamczer study had positive serology at enrollment. No conclusions about toxoplasmosis prophylaxis can be made from these studies.

Can we realistically continue to expect large-scale, long-term clinical trials to answer all of our questions about PCP prophylaxis? Unfortunately, the answer is probably no: It may not be feasible to delineate the exact hierarchy of preventive treatments. A search for new agents or different regimens for prophylaxis is urgently needed. Perhaps future clinical trials should focus on the efficacy of administering aerosolized pentamidine more often, perhaps every 2 weeks. Alternatively, studies might consider staged therapy, either starting with aerosolized pentamidine and continuing with systemic prophylaxis (as the CD4+ lymphocytes decline < 100 × 106L, or after breakthrough PCP) or starting with initial systemic therapy and then continuing with a combination of systemic therapy and aerosolized pentamidine. We need to focus on maintaining the best prophylactic regimen as the risk for PCP increases with advancing immunosuppression.

A pragmatic approach to primary prophylaxis in clinical practice is to enthusiastically start systemic therapy with the "gold" standard, TMP-SMX. I favor a regimen of 1 double-strength TMP-SMX tablet either daily or 3 times a week to maintain efficacy and to minimize adverse events. Rather than maintaining a rigid regimen, it is important to have a flexible approach to the various prophylactic options, choosing the best regimen on a case-by-case basis, as was shown by Bozzette and colleagues. It is important to ensure that all those at risk continue to receive prophylaxis. In the face of adverse events or poor compliance with systemic therapy, monthly aerosolized pentamidine should not be forgotten.

R. Andrew McIvor, MD
University of TorontoToronto, Ontario, Canada


Reference

1. USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. U.S. Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA). MMWR Morb Mortal Wkly Rep. 1999;48(RR-10):1-59, 61-6.