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Therapeutics

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

ACP J Club. 1995 Sept-Oct;123:40. doi:10.7326/ACPJC-1995-123-2-040


Source Citation

Bozzette SA, Finkelstein DM, Spector SA, et al. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. N Engl J Med. 1995 Mar 16;332:693-9.


Abstract

Objective

To evaluate the effectiveness of 3 treatment strategies for the prevention of a first episode of Pneumocystis carinii pneumonia (PCP) in patients infected with the human immunodeficiency virus (HIV).

Design

Randomized controlled trial with median 39-month follow-up.

Setting

Multiple centers in the United States.

Patients

843 patients (mean age 36 y, 93% men) with HIV infection and a CD4+ cell count < 200 × 106/L who had tolerated ≥ 1 month of zidovudine therapy at a dose of ≥ 500 mg/d. Exclusion criteria were history of PCP or toxoplasmosis; active bacterial or mycobacterial infections; weight < 40 kg; hemoglobin levels < 95 g/L; absolute neutrophil levels < 1.0 × 109/L; platelet levels < 75 × 109/L; creatinine clearances < 0.83 mL/s; serum aminotransferase levels > 10 times the upper limit of normal; evidence of glucose-6-phosphate dehydrogenase deficiency; pregnancy; lactation; anaphylactic-type reactions to the study drugs or related compounds; prophylaxis against PCP within the previous 4 weeks; or current active primary therapy for an infection or cancer.

Intervention

Patients received zidovudine plus 1 of 3 prophylactic agents: trimethoprim, 160 mg, plus sulfamethoxazole, 800 mg, twice daily (TMP-SMX) (n = 276); dapsone, 50 mg twice daily (n = 288); or aerosolized pentamidine, 300 mg every 4 weeks (n = 278). Allowance was made for dosage reduction or crossover to an alternate treatment in cases of intolerance.

Main outcome measures

PCP and toxoplasmosis.

Main results

Analysis was by intention to treat. Among 137 reported cases of PCP, 42 (31%) occurred in the TMP-SMX group, 41 (30%) occurred in the dapsone group, and 54 (39%) occurred in the aerosolized pentamidine group (P = 0.22). Among patients entered into the trial with a CD4+ cell count < 100 × 106/L, PCP occurred more frequently in those receiving aerosolized pentamidine than in those receiving TMP-SMX or dapsone (P = 0.04). Toxoplasmosis developed in < 3% of patients. Only 21% of patients in the TMP-SMX group and 25% of patients in the dapsone group compared with 88% of patients in the aerosolized pentamidine group completed the study receiving the original dose of the drug to which they had originally been assigned.

Conclusions

The 3 treatment strategies studied had similar effectiveness in preventing Pneumocystis carinii pneumonia in patients with advanced human immunodeficiency virus infection. Starting treatment with trimethoprim-sulfamethoxazole or high-dose dapsone rather than aerosolized pentamidine was superior in patients with a CD4+ cell count < 100 × 106/L.

Sources of funding: AIDS Clinical Trials Group of the NIAID and National Center for Research Resources.

For article reprint: Dr. S.A. Bozzette, San Diego Veterans Affairs Medical Center, Mail Code 111N-1, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. FAX 858-552-4321.


Commentary

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