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


Therapeutics

Rifabutin prophylaxis reduced Mycobacterium avium complex infection in AIDS

ACP J Club. 1994 Mar-April;120:37. doi:10.7326/ACPJC-1994-120-2-037


Source Citation

Nightingale SD, Cameron DW, Gordin FM, et al. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. N Engl J Med. 1993 Sep 16;329:828-33.


Abstract

Objective

To determine the effectiveness of rifabutin prophylaxis in reducing Mycobacterium avium complex infection in patients with the acquired immunodeficiency syndrome (AIDS).

Design

2 randomized, double-blind, placebo-controlled trials with a mean duration of therapy of 223 days in study 1 and 188 days in study 2. At the end of each study, patients in whom M. avium complex bacteremia had not developed were offered open-label rifabutin.

Setting

Multicenter study in North America.

Patients

590 patients (mean age 37 y, 97% men) were enrolled in study 1 and 556 patients (mean age 39 y, 98% men) were enrolled in study 2. In both studies, the patients had a previous AIDS-defining event other than disseminated M. avium complex infection, a CD4+ lymphocyte count ≤ 200/mm3, a negative tuberculin skin test, ≥ 4 weeks therapy with either zidovudine or didanosine, and antipneumocystis prophylaxis for ≥ 4 weeks before enrollment. Exclusion criteria were previous or current mycobacterial infection; antimycobacterial therapy during the previous 4 weeks; abnormal hematologic, hepatic, or renal function; or a history of allergy to rifamycin.

Intervention

Patients in both studies were randomly assigned to either 300 mg of rifabutin (study 1 n = 292, study 2 n = 274) or placebo (study 1 n = 298, study 2 n = 282) daily.

Main outcome measures

M. avium complex bacteremia, signs and symptoms associated with disseminated M. avium complex infection, adverse events, hospitalization, and survival.

Main results

In study 1, M. avium complex bacteremia developed in 51 patients (17%) initially assigned to receive placebo and 24 patients (8%) initially assigned to receive rifabutin { P = 0.001}* (Table). In study 2, bacteremia developed in 51 patients (18%) in the placebo group compared with 24 patients (9%) in the rifabutin group { P = 0.001}* (Table). Fever, fatigue, Karnofsky performance score, anemia, alkaline phosphatase elevation, and hospitalization were reduced by rifabutin prophylaxis, but the groups did not differ in weight loss, night sweats, or diarrhea. The incidence of adverse events and overall survival were similar.

Conclusion

Rifabutin prophylaxis reduced the frequency of disseminated Mycobacterium avium complex infection in patients with AIDS and CD4+ counts ≤ 200/mm3.

Sources of funding: Adria Laboratories and the Canadian HIV Clinical Trials Network.

For article reprint: Dr. F.M. Gordin, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA. FAX 202-745-8301.

*P values calculated from data in article.


Table. Rifabutin vs placebo for Mycobacterium avium complex infection in AIDS†

Outcomes Rifabutin Placebo RRR (95% CI) NNT (CI)
Bacteremia in study 1 at a mean of 223 d 8% 17% 52% (25 to 70) 12 (7 to 28)
Bacteremia in study 2 at a mean of 188 d 9% 18% 52% (24 to 69) 11 (7 to 27)

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


Commentary

The incidence of M. avium complex bacteremia has decreased since the advent of highly active antiretroviral therapy (1), yet there are still large numbers of patients who may benefit from prophylaxis of M. avium bacteremia. Although Nightingale and colleagues were unable to show a statistically significant reduction in mortality, a subsequent publication with a longer follow-up of the 2 original cohorts showed a statistically significant decrease in the relative hazard for dying in patients treated with rifabutin compared with placebo (2).

Because of rifabutin's cost, potential drug interactions because of its ability to induce cytochrome P 450 metabolism, and concerns about creating rifampin resistance in patients co-infected with M. tuberculosis, other prophylactic agents have been studied since this study was published. Pierce and colleagues showed that clarithromycin, 500 mg twice daily, was better than placebo in preventing M. avium complex bacteremia as well as death (3). Havlir and colleagues showed that azithromycin, 1200 mg weekly, was better than rifabutin (4). The combination of azithromycin and rifabutin was even better, yet the incidence of dose-limiting toxicity was also increased.

Based on these studies, the U.S. Public Health Service Task Force on Prophylaxis and Therapy for M. avium complex recommended that clarithromycin or azithromycin be the preferred prophylactic agents and rifabutin should be reserved as a second-line drug in patients who are macrolide intolerant (5). Such prophylaxis seems to be the most beneficial in patients with CD+ counts < 50/mm3. It is hoped that the population of patients with such severe immunodeficiency will continue to decrease because of further progress in antiretroviral therapy.

Fred A. Zar, MD
Francis Hospital of EvanstonMaywood, Illinois, USA


References

1. Michaels SH, Clark R, Kissinger P. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection [Letter]. N Engl J Med. 1998;339:405-6.

2. Moore RD, Chaisson RE. Survival analysis of two controlled trials of rifabutin prophylaxis against Myocobacterium avium complex in AIDS. AIDS. 1995;9:1337-42.

3. Pierce M, Crampton S, Henry D, et al. A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced acquired immunodeficiency syndrome. N Engl J Med. 1996;335:384-91.

4. Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group. N Engl J Med. 1996;335:392-8.

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.