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Therapeutics

Meta-analysis: Low-dose sulfamethoxazole-trimethoprim is an effective regimen for P. carinii prophylaxis in HIV infection

ACP J Club. 1996 July-Aug;125:12. doi:10.7326/ACPJC-1996-125-1-012


Source Citation

Ioannidis JP, Cappelleri JC, Skolnik PR, Lau J, Sacks HS. A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens. Arch Intern Med. 1996 Jan 22;156:177-88. [PubMed ID: 8546551]


Abstract

Objective

To evaluate, using meta-analysis, the efficacy and tolerability of different strategies of prophylaxis of Pneumocystis carinii pneumonia (PCP) in patients with HIV infection.

Data sources

English-language studies were identified through MEDLARS. Abstracts from the International AIDS Conferences and the National Conferences on Human Retroviruses were also included. The bibliographies of identified articles were scanned to identify additional studies.

Study selection

Studies were selected if they were randomized trials that used sulfamethoxazole-trimethoprim, dapsone-based regimens, or aerosolized pentamidine in adult patients and that compared different prophylactic regimens directly or with placebo. Both primary and secondary prophylaxis trials were included.

Data extraction

Extracted data included the number of PCP episodes, PCP-related deaths, toxoplasmosis events, all deaths, and number of patients who discontinued their original treatments because of side effects.

Main results

35 studies involving 6538 patients met the selection criteria. PCP events were reduced in patients given any form of prophylaxis compared with placebo {relative risk reduction (RRR) 68%, 95% CI 54% to 77%}*. In the comparison of different prophylactic regimens, sulfamethoxazole-trimethoprim was superior to aerosolized pentamidine with a 42% (CI 24% to 55%) overall reduction in prophylaxis failures. Regardless of dose (range, 2 double-strength tablets/d to 1 double-strength tablet 3 times/wk), sulfamethoxazole-trimethoprim was almost universally effective for patients who tolerated it. There was a nonsignificant trend toward fewer treatment failures with sulfamethoxazole-trimethoprim compared with dapsone-based regimens {RRR 39%, CI 210% to 66%}*. Aerosolized pentamidine and dapsone-based regimens were equivalent in effectiveness. Sulfamethoxazole-trimethoprim or dapsone regimens also reduced the number of cases of toxoplasmosis by 33% (CI 12% to 50%) compared with aerosolized pentamidine, based on an intention-to-treat analysis. Compared with aerosolized pentamidine, however, oral regimens were 5 times more likely overall to be discontinued because of toxic reactions. The risk for discontinuing sulfamethoxazole-trimethoprim because of side effects decreased by 43% (CI 30% to 54%) when 1 double-strength tablet was given 3 times per week instead of daily. No difference existed in overall mortality among the various regimens.

Conclusions

Sulfamethoxazole-trimethoprim is the superior regimen for Pneumocystis carinii prophylaxis in patients with HIV infection. Low doses of sulfamethoxazole-trimethoprim (1 double-strength tablet given 3 times per week or 1 single-strength tablet daily) can improve drug tolerance without losing effectiveness.

Sources of funding: National Institutes of Health and the Agency for Health Care Policy and Research.

For article reprint: Dr. J. Lau, Division of Clinical Care Research, New England Medical Center Hospitals, Box 63, 750 Washington Street, Boston, MA 02111, USA. FAX 617-636-8023.

*Numbers calculated from data in article.


Commentary

This careful meta-analysis makes a valuable contribution by quantifying the relative benefits and risks of the different primary prophylactic regimens. Several clear findings emerge. First, sulfamethoxazole- trimethoprim is more effective than either aerosolized pentamidine or dapsone in preventing both PCP and toxoplasmosis. Second, discontinuing medication because of toxic effects was 5 times more frequent in patients treated with either oral sulfamethoxazole- trimethoprim or dapsone than with aerosolized pentamidine; however, the risk for toxic effects decreased by 43% if 1 double-strength tablet of sulfamethoxazole-trimethoprim was given 3 times a week instead of daily. This dose reduction was not accompanied by a reduction in efficacy.

What lessons do these findings have for clinical practice? When primary prophylaxis is indicated (1), low-dose sulfamethoxazole- trimethoprim (i.e., 1 double-strength tablet 3 times a week or 1 single-strength tablet each day) should be adopted as the standard first-line regimen. This approach, combined with the use of more refined protocols for desensitization, may reduce the number of patients who cannot tolerate this drug. For those patients who remain intolerant, do not respond to highly active antiretroviral therapy, and continue to need prophylaxis, the results of this meta-analysis suggest that a dose increase in aerosolized pentamidine from 300 mg per month to 300 mg twice per month would result in a 50% decrease in prophylaxis failures. In contrast, although lower doses of dapsone were better tolerated than higher doses, some efficacy was lost. The dose of dapsone should therefore be determined on a case-by-case basis according to baseline hematologic status and use of interacting drugs, such as didanosine.

Questions remain about whether these findings can be extrapolated to secondary prophylactic regimens as well as about the value of desensitization and the contribution of other potentially useful prophylactic regimens such as pyrimethamine-sulfadoxine (Fansidar), intramuscular pentamidine, clindamycin- primaquine, and atovaquone.

Philippa J. Easterbrook, MD
Chelsea and Westminster HospitalLondon, England, UK


Reference

1. Kovacs JA, Masur H. Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med. 2000;342:1416-29.