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Therapeutics

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

ACP J Club. 1993 May-June;118:84. doi:10.7326/ACPJC-1993-118-3-084


Source Citation

Hardy WD, Feinberg J, Finkelstein DM, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. AIDS Clinical Trials Group Protocol 021. N Engl J Med. 1992 Dec 24;327:1842-8.


Abstract

Objective

To compare the efficacy and safety of aerosolized pentamidine with trimethoprim-sulfamethoxazole (TMP-SMX) for secondary prophylaxis against Pneumocystis carinii pneumonia (PCP) in patients with AIDS.

Design

Randomized controlled trial with median follow-up of 17 months.

Setting

23 AIDS Clinical Trial Group sites.

Patients

Patients with HIV infection who had recovered from confirmed PCP. Exclusion criteria were previous severe intolerance to study drugs; compromised hematologic, hepatic, or renal function; glucose-6-phosphate dehydrogenase deficiency; Karnofsky score < 60; pregnancy or lactation; or age < 12 years old. 310 patients (mean age 36 y, 94% men) were studied with 90% follow-up.

Intervention

All patients received zidovudine (1200 mg/d initially and 600 mg/d after March 1990). 156 patients were randomized to aerosolized pentamidine, 150 mg every 2 weeks until July 1989 and then 300 mg every 4 weeks. 154 patients were randomized to TMP-SMX (trimethoprim, 160 mg/d, and sulfamethoxazole, 800 mg/d). TMP-SMX and zidovudine doses were modified using toxicity-managing algorithms.

Main outcome measures

Death and recurrence of PCP either morphologically or presumptively diagnosed. Secondary end points were adverse effects and discontinuation of medications. Patients were seen every 2 weeks for 12 weeks and then every 4 weeks.

Main results

The groups did not differ for mortality (47 deaths in the group initially randomized to pentamidine vs 43 in the TMP-SMX group) or for frequency and severity of hematologic and hepatic toxicities. Patients in the TMP-SMX group had fewer PCP recurrences { P < 0.001}* (Table). The estimated 24-month recurrence rate for PCP was 36% in the pentamidine group and 15% in the TMP-SMX group (P < 0.001). The risk for recurrence of PCP for those taking pentamidine was 3.5 (95% CI 1.7 to 6.2) compared with those taking TMP-SMX. 42 patients taking TMP-SMX and 6 taking pentamidine switched treatments.

Conclusion

Patients with AIDS and previous Pneumocystis carinii pneumonia had fewer recurrences of P. carinii pneumonia when taking trimethoprim-sulfamethoxazole compared with those who took aerosolized pentamidine.

Sources of funding: National Institutes of Health and AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases.

For article reprint: Dr. R.S. Holzman, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. FAX 212-263-7369.

* P value calculated from data in article.


Table. Trimethoprim-sulfamethoxazole (TMP-SMX) vs aerosolized pentamidine in AIDS†

Outcome at a median of 70 months TMP-SMX Aerosolized pentamitine RRR (95% CI) NNT (CI)
Pneumocystis carinii pneumonia 9% 23% 61% (31 to 78) 8 (5 to 17)

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


Commentary

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

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.