There have been a number of important developments in the prevention of Mycobacterium avium complex disease in patients with HIV infection since the publication of the US Public Health Service/Infectious Disease Society of America guidelines for prevention last summer (see
Moore News, September 1995). In October 1995, the Food and Drug Administration approved clarithromycin at a dose of 500 mg twice daily for MAC prophylaxis. This was based on a placebo-controlled study in patients with HIV infection and CD4 counts <100 that showed that clarithromycin reduced the incidence of MAC by 69%, reduced the incidence of Pneumocystis carinii pneumonia, serious bacterial infections and giardiasis, and prolonged survival. Among patients who failed clarithromycin prophylaxis in this study, however, the prevalence of clarithromycin-resistant MAC isolates was 58%.
A study published in the December issue of AIDS (R.D. Moore and R.E. Chaisson, Survival analysis of two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex in AIDS, Vol. 9, pp. 1337-42) suggested that MAC prophylaxis with rifabutin was associated with improved survival. The study followed all patients originally enrolled in the rifabutin trials and analyzed the impact of rifabutin use on survival both during the study and after patients were offered open label drug. By looking at the open label use of rifabutin, approximately double the observation time was available. The results showed that after controlling for CD4 count, Karnofsky score and other conditions associated with mortality, rifabutin use reduced the risk of death by 26%. This analysis is consistent with the study of Pierce and associates discussed above, demonstrating improved survival from the prevention of MAC.
At the 3rd National Conference on Retroviruses and Opportunistic Infections in January 1996, three important new studies on MAC prophylaxis were also presented. The results of these trials will result in major changes in our approach to prevention of MAC.
Oldfield and coworkers reported a placebo-controlled trial of azithromycin 1200 mg once weekly for patients with HIV and a CD4 count <100 (median 44). One hundred seventy four patients were followed a median of 340 to 400 days, with monthly blood cultures. Of the 85 patients treated with azithromycin, nine (11%) developed MAC during follow up, compared to 22/89 (25%) placebo recipients (p-0.004). The relative reduction in risk of MAC was 65%. Patients treated with azithromycin were also less likely to develop sinusitis, bacterial pneumonia or any bacterial infections. There was no differences in survival, however. Toxicity attributed to treatment was three times more common in patients treated with azithromycin.
Havlir and associates from the California Collaborative Treatment group reported the results of their study comparing weekly azithromycin 1200 mg to rifabutin 300 mg daily versus the combination of both agents. This double-blind, controlled trial followed patients with HIV and CD4 counts <100 for an average of 296 to 344 days. All patients also received one of two doses of fluconazole. The risk of developing MAC was 23% for patients receiving rifabutin, 14% for patients on azithromycin, and 8% for patients on combination therapy. The differences in treatment were highly significant for azithromycin or combination therapy versus rifabutin, and marginal for combination versus azithromycin. Patients receiving azithromycin or combination had lower rates of bacterial infections, as well. Of patients who failed azithromycin alone, 2/18 (11%) had drug-resistant MAC isolates. No patients treated with rifabutin or combination developed resistance. There was no difference in survival between any of the treatment arms.
Benson and colleagues presented the results of ACTG 196/CPCRA 009, a controlled trial of clarithromycin 500 mg twice daily versus rifabutin 450 mg or 300 mg daily versus combination therapy for patients with HIV and CD4 counts <100. Rifabutin was initially given at 450 mg daily, but the dose was lowered to 300 mg daily after cases of uveitis began to appear. 1178 patients were included in the analyses, with a median follow-up of almost 600 days. The rates of MAC were 15% for patients on rifabutin, 9% for patients on clarithromycin, and 7% for patients on clarithromycin and rifabutin. Toxicity was considerably higher in the combination arm, including 23 cases of uveitis. Of patients who developed MAC, clarithromycin resistance was seen in 29% of those failing clarithromycin and 36% of those failing combination therapy. There was no difference in mortality between the groups.
The results of these new studies have important clinical implications. First, it is clear that prevention of MAC prolongs survival in HIV disease, as is true for Pneumocystis. Second, the macrolides appear to be more efficacious than rifabutin in presenting MAC, but emergence of drug-resistance remains a concern. It is not clear if there is any difference between clarithromycin and azithromycin with respect to efficacy based on current data. It is also not clear whether combination therapy with rifabutin and a macrolide is preferable to either agent alone, given considerations of cost and tolerance. Third, there are additional issues to be considered, including drug interactions, dosing schedules and cost-effectiveness, that may shift the balance in choosing prophylaxis. For the current time, clinicians treating patients with CD4 counts <75mm 3 can prescribe MAC prophylaxis with azithromycin 1200 mg weekly, clarithromycin 500 mg twice daily or rifabutin 300 mg daily. Future articles will explore this issue in more detail.