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Two Drugs Might Be Better Than One for Prophylaxis of M. Avium Disease, But Are Any of Them Clarithromycin?

24-29% with resistant bugs

There was a good amount of new data released early last month at the Third Conference on Retroviruses and Opportunistic Infections in Washington, D.C. While it was unlikely that any OI news could compete successfully with the raucous choruses proclaiming protease inhibitors to be the HIV-infected world’s salvation, long-awaited data was presented on two very large studies looking at various drugs in different regimens for the prevention of mycobacterium avium complex (MAC). Michael Marco was there and prepared this report

ACTG 196, chaired by Chicago Rush Medical College’s Connie Benson, was presented to a standing-room-only audience during Tuesday afternoon’s MAC symposium. ACTG 196 (also known as CPCRA 009) was a phase III, prospective, randomized, double-blind study comparing clarithromycin (Biaxin) to rifabutin (Mycobutin) to the two drugs together for the prevention of MAC in HIV-infected individuals with CD4 cell counts less than 100.

The genesis of this three-arm comparative trial grew out of the feeling of many clinicians that while rifabutin has been the standard-of-care for MAC prophylaxis, clarithromycin presented an excellent option. Both are now FDA-approved for the prophylaxis of M. avium disease. Indeed, in the treatment of MAC infection, clarithromycin is generally recognized as the most effective (and necessary) agent in the antimycobacterial combination.

Data from Abbott Labs which was presented at last autumn’s ICAAC conference showed clarithromycin to be extremely effective: a 68% reduction in the risk of developing active MAC infection–and a survival benefit to boot–compared to placebo. Of those persons who “failed” (came down with active MAC or developed MAC bacteremia in their blood) on clarithromycin prophylaxis, however, a whopping 60% were found to have developed clarithromycin-resistant MAC. Had they needlessly squandered their chance to benefit from the antimycobacterial activity of clarithromycin during active MAC infection through an over-zealous, over-cautious preventive strategy? Afterall, if one had to choose, when would one most want the most potent antibiotic on board: when s/he was well or when s/he was ill?

The design of ACTG 196 was meant to shed light on the question of whether (this may sound familiar) combination antibiotic therapy would slow the development of drug-resistant MAC. And for the ACTG 196 participants who developed MAC during the study’s follow-up period, 29% in the clarithromycin alone group were found to have developed resistance to the drug. Not surprisingly, none of those in the rifabutin group had developed resistance to clarithromycin. What was surprising (and a bit disappointing), however, was the discovery that 24% of the people in the combination prophylaxis group (clarithromycin + rifabutin) had become resistant to clarithromycin; thus it seemed that adding rifabutin to single agent clarithromycin did very little toward achieving the goal of slowing the development of clarithromycin resistant MAC.

The results of ACTG 196 leave clinicians and patients alike with the question of how to judge the relative risks and benefits of these two MAC prophylaxis strategies. In preventing an initial active infection of MAC, clarithromycin is clearly superior: ACTG 196 showed that 35 (9%) people in the clarithromycin group developed MAC during the course of the study whereas 59 (15%) of the people in the rifabutin group did. (In the combination prophylaxis group, 7% of the people developed MAC during the study.) But where nearly one third of those who “broke through” have possibly foregone future benefit from clarithromycin’s antimycobacterial activity, that protection comes at a price.

Would azithromycin (Zithromax) be any better?

UC-San Diego’s Diane Havlir posed this question with her Pfizer-sponsored study designed (very similarly to ACTG 196) to compare prophylaxis strategies employing either azithromycin (rather than cousin drug clarithromycin) to rifabutin to the combination of the two in 669 HIV-infected persons with CD4 cell counts less than 100. Her results showed that 11.6% of persons in the rifabutin prophylaxis group developed active MAC compared to 8.8% of those in the azithromycin group and 2.5% of those in the combo group. (The intent-to-treat analysis was not so favorable, where the rate of MAC was 13.9% in the azithromycin group, 23.5% in the rifabutin group and 8.2% in the combination group. There were no differences in survival, and no differences in dose-limiting toxicities.)

When testing those who broke through, however, 2 out of 18 (11%) of those in the azithromycin alone group had developed MAC that was resistant to both azithromycin and clarithromycin. (Since the two drugs are closely related, cross-resistance between azithromycin and clarithromycin is virtually guaranteed.) In the five individuals who broke through in the combination arm, however, none were found to be resistant. Could this become a new prophylactic combination?

The Pfizer study differs significantly from ACTG 196 in that the azithromycin + rifabutin combination regimen turned out to be significantly better at decreasing the risk of MAC than either of the two drugs alone. Also, resistance from single agent azithromycin was much lower than ACTG 196’s rate of resistance to clarithromycin. Better still, when azithromycin was used together with rifabutin, no resistance seemed to emerge.

According to the symposium’s participants, the question of what should really be first-line therapy for MAC prophylaxis might have to wait until we figure out what clarithromycin resistance really means; that is, what effect does clarithromycin resistance have on a person’s clinical prognosis and overall survival. The ACTG’s Mycobacterial Pathogen Study Group is currently engaged in work which will attempt to answer these very questions.

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