Brief Update on the Treatment of Mycobacterium avium Complex (MAC Disease)

Several recent studies have produced important information on the optimal management of MAC disease in patients with HIV infection. Currently, clarithromycin at a dose of 500 mg twice daily is the cornerstone of therapy, though azithromycin at a dose of 600 mg daily may have similar activity. Resistance rapidly develops if these drugs are used alone, and there is complete cross-resistance with clarithromycin and azithromycin. Earlier studies of clarithromycin suggested that doses of >1000 mg twice daily were associated with higher mortality than a dose of 500 mg twice daily [Annals Internal Medicine 1994;121:905]. A study performed by the Community Program for Clinical Research on AIDS (CPCRA) evaluated the efficacy of two doses of clarithromycin in combination regimens for disseminated MAC infections [Cohn et al., XI Int Conf AIDS, LB065]. Patients with disseminated MAC infection were randomly assigned to receive clarithromycin at a dose of either 500 mg BID or 1000 mg BID, in combination with other agents. An independent data safety monitoring board halted the study early after high mortality rates were observed in the patients assigned to the higher dose of clarithromycin (rate: 159 deaths per 100 person years versus 70 deaths per 100 person years). The US Food and Drug Administration had approved clarithromycin for treatment of MAC only at the 500 mg dose.

The addition of ethambutol (15 mg/kg/day) is highly effective in preventing the emergence of resistance to the macrolides. In a study sponsored by Abbott Laboratories, patients treated with clarithromycin and ethambutol had prompt improvement in symptoms and reduction in MAC levels in the blood (mostly to negative) within several months [Chaisson et al., 3rd Nat Conf on Retrovirus Opport Infect]. Only 1/45 patients on this regimen developed resistance to clarithromycin.

A study by Dautzenberg and associates from France showed that rifabutin alone reduced MAC colony counts in blood by 0.8 logs over a two week period [Am J Respir Crit Care Med 1996;153(Suppl):A329]. This was felt to indicate substantial activity of rifabutin and suggests a role for this agent in combination regimens. This is confirmed by another recent trial. The Canadian HIV Clinical Trials Network has published the results of a study that compared two regimens for the treatment of MAC [Shafran et al. N Engl J Med 1996; 335:377]. Patients who received a three-drug regimen of clarithromycin, rifabutin and ethambutol had significantly better microbiologic responses and better survival than patients treated with a four-drug regimen of rifampin, ethambutol, ciprofloxacin and clofazimine. Although patients receiving rifabutin 600 mg daily had more toxicity (primarily uveitis) than patients receiving 300 mg daily, they also had greater rates of sterilization of blood cultures. A French trial by May and coworkers also shows the efficacy of the combination of clarithromycin, rifabutin and ethambutol [XI Int Conf AIDS].

Clofazimine has been found in several studies to have minimal to no activity in treating MAC, and may be dangerous. The Abbott trial mentioned above found patients who received clofazimine in addition to clarithromycin and ethambutol had significantly higher mortality than patients who only received the latter two drugs. Studies by May and coworkers [XI Int Conf AIDS] and Dube and associates [3rd Nat Conf Retrovirus Opport Inf] show that clofazimine is inferior to other combinations in preventing relapse and emergence of resistance.

Based on the emerging information, treatment of MAC infection initially should be with clarithromycin 500 mg twice daily (or azithromycin 600 mg daily) plus ethambutol 15 mg/kg/daily with or without rifabutin (300-450 mg daily). In patients who may have macrolide resistant disease, the three drug combination should be used. Treatment of relapsed disease due to resistance is difficult, as there are no additional agents with proved activity. One option is to add two new agents, such as amkacin and ciprofloxacin, though the efficacy of such manuevers is unknown. Ongoing studies are looking at two- versus three-drug combinations for initial therapy, as well as several "salvage" regimens. The role of immunotherapy in treating MAC is also under investigation. The substantial progress made in the past several years has had an emormous impact on the quality of life for patients with MAC disease.