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Therapeutics

Azithromycin, with or without rifabutin, prevented M. avium complex infection

ACP J Club. 1997 Jan-Feb;126:9. doi:10.7326/ACPJC-1997-126-1-009


Source Citation

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


Abstract

Objective

To compare the prophylactic effectiveness of azithromycin alone, rifabutin alone, and both drugs combined for Mycobacterium avium complex infection in patients with HIV infection.

Design

Randomized, double-blind, controlled trial with median 514-day follow-up.

Setting

12 centers in the United States.

Patients

693 patients who were ≥ 18 years of age (mean age 38 y, 95% men) and HIV seropositive, with CD4+ cell counts < 100 cells/mm3 within 1 year of randomization. Other inclusion criteria were neutrophil count ≥ 500 cells/mm3; platelet count ≥ 50 000 cells/mm3; serum creatinine and bilirubin levels < 3 times the upper limit of normal; serum aminotransferase levels < 5 times the upper limit of normal; normal chest radiograph; Karnofsky score > 60; no opportunistic infection; and no hypersensitivity to study drugs. Patients with suspected M. avium infection or pregnant or lactating women were excluded. 96% of patients were included in the analysis.

Intervention

Patients were allocated to rifabutin, 300 mg daily (n = 236); azithromycin, 1200 mg weekly (n = 233); or both drugs (n = 224).

Main outcome measures

Development of M. avium complex infection, survival, and adverse effects.

Main results

In an intention-to-treat analysis, M. avium complex infection developed in 23.3% of patients who received rifabutin, 13.9% of patients who received azithromycin, and 8.3% of patients who received combination therapy. Compared with rifabutin, M. avium complex infection developed in fewer patients who received combination therapy (P < 0.001) or azithromycin (P = 0.008). The combination was more effective than azithromycin alone (P = 0.03) but also had more dose-limiting toxic effects (P = 0.03). {For azithromycin compared with rifabutin, the absolute risk reduction of 9.4% means that 11 patients would need to be treated with azithromycin (rather than rifabutin) for approximately 1 year to prevent 1 additional patient from developing M. avium complex infection, 95% CI 6 to 45; the relative risk reduction was 40%, CI 11% to 60%.}* The groups did not differ for survival. 85 (38%), 83 (37%), and 81 (37%) patients died in the rifabutin, azithromycin, and combination therapy groups, respectively. More adverse events occurred in patients who received azithromycin (88%) or combination therapy (90%) compared with patients who received rifabutin (76%) (P < 0.001 for both comparisons). Most adverse events were caused by gastrointestinal toxic effects.

Conclusion

Azithromycin alone and in combination with rifabutin was more effective than rifabutin alone in preventing the development of M. avium complex infection in patients with HIV infection.

Sources of funding: California Collaborative Treatment Group; Pfizer Central Research; Adria Laboratories.

For article reprint: Dr. D.V. Havlir, UCSD Treatment Center, University of California, San Diego, 2760 Fifth Avenue, Suite 300, San Diego, CA 92103, USA. FAX 619-298-0177.

*Numbers calculated from data in article.


Commentary

Triple therapy cleared M. avium complex infection better than quadruple therapy in HIV infectionandClarithromycin reduced rates of M. avium complex infection and mortality in AIDS

It has been apparent for some time that multidrug regimens are required to treat M. avium complex infection, both for efficacy and to prevent the emergence of resistance to individual agents. At the time their study was initiated, Shafran and colleagues compared the 2 regimens that were deemed most likely to be efficacious. Their results indicate that 3 drugs (clarithromycin, rifabutin, and ethambutol) can be better than 4 (ciprofloxacin, clofazimine, rifampin, and ethambutol).

Clarithromycin and azithromycin are considered to be ideal antibiotics for the treatment of M. avium infections. Clarithromycin has been shown to have a postantibiotic effect against M. avium, ranging from 5.5 to 18 hours. As monotherapy, clarithromycin is associated with a greater reduction from baseline in M. avium blood culture colony counts than is any other single agent. However, because clarithromycin resistance develops in about 50% of blood culture isolates taken from patients receiving clarithromycin alone, the use of combined therapy is mandated.

Despite the therapeutic success of the 3-drug combination, the Shafran study raises several issues. Clarithromycin increases the serum level of rifabutin, and the incidence of uveitis caused by rifabutin was 39% at the original dose of 600 mg daily. The incidence of uveitis was reduced to 6% after the rifabutin dose was decreased to 300 mg daily, but the lower dose had less efficacy, as indicated by substantially poorer clearance of M. avium bacteremia. (The 3-drug regimen with low-dose rifabutin, however, was still superior to the 4-drug regimen.) Uveitis may begin anytime between 2 weeks and 7 months after rifabutin is initiated. 600 mg of rifabutin daily, given for 4 weeks and followed by 300 mg daily, is a logical treatment strategy; however, it must be recognized that this regimen has not been tested.

The best dose regimen of clarithromycin is also unclear. The Community Programs for Clinical Research on AIDS (CPCRA027) 4-group study was designed to compare 3-drug regimens that all contained clarithromycin and ethambutol but differed in the third drug that was used (rifabutin vs clofazamine) and in the clarithromycin dosage (500 vs 1000 mg twice daily) (1). The higher-dose groups were eliminated when a preliminary analysis indicated a reduced survival rate with the regimens that contained the higher clarithromycin dose. Rifabutin reduces clarithromycin levels by about one half, so the 1000-mg twice-daily dosage used by Shafran and colleagues may be equivalent to the 500-mg twice-daily dosage used in the CPCRA027 trial. However, there was no indication that mortality was reduced in the patients who received rifabutin, 600 mg daily, and clarithromycin, 1000 mg twice daily, compared with the patients who received the lower dose of rifabutin. The adverse clarithromycin-rifabutin interaction makes any estimate of levels imprecise if, for example, the patient takes the wrong dose or misses a few doses of either drug.

The studies on the prophylaxis of M. avium disease suggest several alternative drugs for this purpose, each of which has its own drawbacks. Pierce and colleagues show that, in patients with a CD4+ count of 100 cells/mm3, clarithromycin, 500 mg daily, reduced both the incidence of disseminated M. avium infections and mortality rates. This antibiotic had relatively little toxicity; minor taste perversion and gastrointestinal disturbances occurred. The incidence of resistant M. avium isolates, however, was 58% in those who developed disseminated M. avium infection despite prophylaxis compared with 0% in the placebo group.

Havlir and colleagues found that once-weekly azithromycin, alone or in combination with daily rifabutin, was a more effective prophylaxis than was daily rifabutin alone. Only 11% of breakthrough isolates from patients who received azithromycin were resistant to azithromycin (and clarithromycin). Whether this is truly different than the 58% incidence of resistance in breakthrough isolates from patients receiving daily clarithromycin remains to be determined. None of the 21 isolates from patients who received rifabutin were resistant to rifabutin, and none of the 5 isolates in patients assigned to combination therapy were resistant to either rifabutin or azithromycin. The primary side effect of azithromycin is gastrointestinal toxicity; dose-limiting toxic effects were substantially more common in the combination group than in the group receiving azithromycin alone.

We are left with a choice between 1) a prophylactic agent that has high efficacy (clarithromycin or azithromycin) but produces resistance to the most effective therapeutic antibiotics for the few patients with breakthrough isolates and 2) a drug, rifabutin, that is less effective but produces almost no resistant M. avium. Since these studies were done, it has been recommended that M. avium prophylaxis should begin at a CD4+ count of ≤ 75 cells/mm3 in patients with an AIDS-defining illness and at ≤ 50 cells/mm3 in those without (rather than < 100 cells/mm3), thus reducing the total number of patients who require prophylaxis. Prophylaxis should not be initiated without reasonable evidence that the patient is free of active tuberculosis and active M. avium infection, both of which require therapy with multiple agents. Weekly azithromycin is the least expensive regimen. If the patient has preexisting liver disease, it is probably best to avoid rifabutin. Potential drug interactions with the protease inhibitors may influence the choice of drug or dose. As a final consideration, if the macrolides are used for prophylaxis, we must be prepared to treat the occasional patient with breakthrough M. avium infection with less-than-ideal therapy.

John N. Dowling, MD
University of Pittsburgh School of MedicinePittsburgh, Pennsylvania, USA


Reference

1. Cohn DL, Fisher E, Franchio B, et al. Comparison of two doses of clarithromycin in a randomized trial for four 3-drug regimens for treatment of disseminated M. avium complex disease in AIDS: excess mortality associated with high-dose clarithro-mycin. In: XIth International Conference on AIDS; July 1-12, 1996; Vancouver, BC. Abstract LB.B.6025.