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Therapeutics

Triple therapy cleared M. avium complex infection better than quadruple therapy in HIV infection

ACP J Club. 1997 Jan-Feb;126:7. doi:10.7326/ACPJC-1997-126-1-007


Source Citation

Shafran SD, Singer J, Zarowny DP, et al., for the Canadian HIV Trials Network Protocol 010 Study Group. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. N Engl J Med. 1996 Aug 8;335:377-83.


Abstract

Objective

To compare the effectiveness of triple therapy with that of quadruple therapy in treating Mycobacterium avium complex bacteremia in patients with HIV infection.

Design

Randomized controlled trial.

Setting

24 HIV clinics in Canada.

Patients

187 patients (mean age 38 y, 94% men) who were ≥ 16 years of age, were HIV-seropositive, and had M. avium complex mycobacteremia. Exclusion criteria included non- M. avium complex mycobacteremia; previous therapy for M. avium complex; Karnofsky score < 20; expected survival < 6 weeks; abnormal creatinine, aspartate aminotransferase, or total bilirubin levels; or potential for pregnancy.

Intervention

Patients were stratified according to previously received prophylaxis with rifabutin and were allocated to triple therapy (n = 97) or quadruple therapy (n = 90). Triple therapy included rifabutin, 600 mg daily (later reduced to 300 mg); clarithromycin, 1000 mg twice daily; and ethambutol once daily, 800 mg, 1200 mg, or 1600 mg, depending on body weight. Quadruple therapy consisted of rifampin, 600 mg daily; clofazimine, 100 mg daily; ciprofloxacin, 750 mg twice daily; and ethambutol given as for triple therapy.

Main outcome measures

Clearance of M. avium complex bacteremia, survival, and change in symptoms (assessed by 8 questions on the Medical Outcome Survey adapted for HIV [MOS-HIV]).

Main results

At 12 weeks, M. avium complex bacteremia was cleared in more patients who received triple therapy than in patients who received quadruple therapy (69% vs 29%, P < 0.001). {This absolute risk improvement of 40% means that 2 patients would need to be treated with triple therapy (rather than quadruple therapy) for 12 weeks for 1 additional patient to achieve clearance, 95% CI 2 to 4; the relative risk improvement was 139%, CI 71% to 244%.}* Median survival was 65% longer in patients who received triple therapy compared with patients who received quadruple therapy (8.6 vs 5.2 mo, P = 0.001). Changes in the MOS-HIV symptom scores from baseline to week 12 favored patients who received triple therapy compared with quadruple therapy (P = 0.03). Reversible uveitis developed in 28% of patients receiving triple therapy and was associated with the higher dose of rifabutin; uveitis did not occur in patients receiving quadruple therapy. Among patients in the triple therapy group, clearance of bacteremia was greater with the 600-mg dose than with the 300-mg dose of rifabutin (P = 0.03); however, the dose reduction did not affect survival or alleviation of symptoms.

Conclusion

Triple therapy was more effective than quadruple therapy for clearance of M. avium complex bacteremia in patients with HIV infection.

Sources of funding: Health Canada; Pharmacia and Upjohn Canada; Abbott Laboratories.

For article reprint: Dr. S.D. Shafran, Division of Infectious Diseases, Department of Medicine, University of Alberta, 2E4.11 Walter C. Mackenzie Health Sciences Centre, 8440-112 Street, Edmonton, AB T6G 2B7, Canada. FAX 403-492-7137.

*Numbers calculated from data in article.


Commentary

Clarithromycin reduced rates of M. avium complex infection and mortality in AIDSandAzithromycin, with or without rifabutin, prevented M. avium complex infection

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 azi-thromycin. 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 clarithromycin. In: XIth International Conference on AIDS; July 1-12, 1996; Vancouver, BC. Abstract LB.B.6025.