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Therapeutics

Trimethoprim-sulfamethoxazole was better than aerosolized pentamidine in reducing the incidence of primary Pneumocystis carinii pneumonia in HIV infection

ACP J Club. 1993 May-June;118:85. doi:10.7326/ACPJC-1993-118-3-085


Source Citation

Schneider MM, Hoepelman AI, Schattenkerk JK, et al. A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. N Engl J Med. 1992 Dec 24;327:1836-41.


Abstract

Objective

To compare the efficacy and safety of aerosolized pentamidine with trimethoprim-sulfamethoxazole (TMP-SMX) for primary prophylaxis against Pneumocystis carinii pneumonia (PCP) in persons with human immunodeficiency virus (HIV) infection and CD4 counts < 200/mm3.

Design

Randomized controlled trial with follow-up of at least 1 year.

Setting

Outpatient clinics in 12 Dutch hospitals and 1 Danish hospital.

Patients

215 patients (mean age 38 y, 95% men) who had a Karnofsky index of ≥ 60 and were ≥ 16 years old. Exclusion criteria were TMP-SMX or pentamidine in the previous 2 months, previous PCP, intolerance to the study drugs, neutrophil count < 1000/mm3, platelet count < 50 000/mm3, serum creatinine level > 4.5 mg/dL, or serum alanine or aspartate aminotransferase level > 3 times the upper limit of normal.

Intervention

Patients were randomized to 3 groups: aerosolized pentamidine isethionate, 300 mg every 4 weeks (n = 72); TMP-SMX (trimethoprim, 80 mg/d, and sulfamethoxazole, 400 mg/d) (n = 72); or TMP-SMX (trimethoprim, 160 mg/d, and sulfamethoxazole, 800 mg/d) (n = 71).

Main outcome measures

The major end point was morphologically proven PCP. Patients were examined every 4 weeks for symptoms and adverse events.

Main results

Fewer patients developed PCP in the 2 TMP-SMX groups than those who received pentamidine (P = 0.002) (Table). The cumulative incidence of PCP in the pentamidine group was 11%/yr (95% CI 4% to 23%). Adverse effects that required discontinuation of treatment occurred in 2 patients taking pentamidine and in 17 and 18 patients taking low- and high-dose TMP-SMX, respectively. Adverse effects occurred sooner in the high-dose TMP-SMX group (mean 16 vs 57 d, P = 0.02). At 3 months the cumulative incidence of adverse effects in the high-dose TMP-SMX group was 26% (CI 17% to 38%); in the low-dose group, 21% (CI 12% to 32%); and in the pentamidine group, 0%. 8 patients in the pentamidine group and 5 in each of the TMP-SMX groups died. No patients who withdrew or died had developed PCP.

Conclusions

For patients with HIV infection, trimethoprim-sulfamethoxazole compared with aerosolized pentamidine was more effective in reducing the incidence of P. carinii pneumonia. Adverse effects were higher in the trimethoprim-sulfamethoxazole groups, with adverse effects occurring sooner in the high-dose group.

Sources of funding: Dutch Ministry of Public Health and Rhône-Poulenc Pharma.

For article reprint: Dr. M.M. Schneider, University Hospital Utrecht, F02.126, Heidelberglaan 100, 3584 CX Utrecht, Netherlands. FAX 31-302-518-328.


Table. Trimethoprim-sulfamethoxazole (TMP-SMX) vs aerosolized pentamidine at <1 year in HIV infection*

Outcome TMP-SMX Aerosolized pentamidine RRR NNT
Pneumocystis carinii pneumonia 0% 8% 100% 13

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


Commentary

Trimethoprim-sulfamethoxazole was better than aerosolized pentamidine in reducing the incidence of Pneumocystis carinii pneumonia in AIDS

Much has changed since the 1992 publication of the studies of Hardy and colleagues, and Schneider and colleagues, related to prophylaxis of PCP in patients with HIV infection. Introduction of protease inhibitors into our anti-retroviral armamentarium has allowed dramatic reductions in plasma HIV viral loads and reconstitution of CD4+ cell numbers that appear to be functionally active (1). This highly active antiretroviral therapy is partly responsible for the decrease in PCP incidence, decrease in AIDS incidence, and decrease in the death rate from AIDS in the United States (2).

However, substantial numbers of HIV-infected individuals continue to be at risk for PCP and these 2 studies have been joined by dozens of others to solidify our understanding of the best prophylactic options. This may best be summarized by 2 meta-analyses that have been recently published (3, 4). The paper by Ioannidis and colleagues reviewed 35 randomized controlled trials of PCP prophylaxis, 19 of which were primary, 8 of which were secondary, and 8 of which were both. TMP-SMX was found to be superior to pentamidine in the prevention of PCP but not in pneumocystis-related mortality, all mortality, or prevention of toxoplasmosis. TMP-SMX was more toxic than pentamidine and led to a 7-fold higher incidence of discontinuation because of side effects. There was a trend toward better prophylactic efficacy and less toxicity with lower doses of TMP-SMX and every-other-day dosing led to less hematologic toxicity and likelihood of discontinuation of the drug.

Bucher and colleagues reviewed 22 randomized control trials. They excluded placebo-control trials. 13 studies were primary prophylaxis, 4 were secondary, and 6 were both. This meta-analysis confirmed the superiority of TMP-SMX over pentamidine with respect to incidence of PCP but also showed a preventative effect on the incidence of subsequent toxoplasma encephalitis. There was a trend towards better tolerance and less incidence of PCP with every-other-day dosing of TMP-SMX in this meta-analysis as well.

These results are reflected in the latest USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with HIV (5). The preferred prophylactic agent is TMP-SMX. Equally strong recommendations are given for the dosing regimen of 1 double-strength tablet per day or 1 single-strength tablet per day. Preference for TMP-SMX is so strong that it is even suggested that patients with previous non-life-threatening allergic reactions to TMP-SMX be rechallenged to see if it is tolerated.

At present, TMP-SMX appears to provide excellent prophylaxis of PCP. Further strides in the prevention of PCP will hopefully come from more potent and prolonged viral suppressive therapies leading to sufficient reconstitution of the immune system to make this opportunistic infection a rare event in persons infected with HIV.

Fred A. Zar, MD
Saint Francis HospitalEvanston, Illinois, USA


References

1. Powderly WG, Landay A, Lederman MM. Recovery of the immune system with antiretroviral therapy. The end of the opportunism? JAMA. 1998;280:72-7.

2. Palella FJ Jr., Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998;338:853-60.

3. Ioannidis JP, Capelleri JC, Skolnik PR, et al. A meta-analysis of the relative efficacy and toxicity of pneumocystis carinii prophylactic regimens. Arch Intern Med. 1996;156:177-88.

4. Bucher HC, Griffith I, Guyatt GH, Opravil M. Meta-analysis of prophylactic treatments against pneumocystis carinii pneumonia and toxoplasma encephalitis in HIV-infected patients. J Acquir Immune Defic Syndr. 1997;15:104-14.

5. USPHS/IDSA Prevention of Opportunistic Infections Working Group. 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep. 1997;46(RR-12):1-46.