GMHC Treatment Issues, Vol. 10, No. 4 - April 1996
Gabriel Torres, M.D.

Several lines of evidence seem to indicate that a few individuals develop MAC from reactivation of an old infection. The preponderance of evidence, however, indicates that most individuals develop MAC following recent acquisition of a virulent MAC strain. Epidemiological studies have found evidence that many patients who contract MAC had new exposure to the bacterium from environmental sources such as tap water or soil.1 The sum of this evidence is inconclusive, and there is no recommendation as to how an individual can avoid exposure to MAC from environmental sources.

The MAC bacteria infects the respiratory system and the gastrointestinal tract, initially forming colonies without causing symptoms. This asymptomatic colonization can lead to dissemination of MAC through the bloodstream (MAC bacteremia) and more aggressive disease. Many experts support treatment of patients who are MAC-colonized but without signs of dissemination in order to prevent spread of the infection via the bloodstream. Virulent MAC strains seem to bind tightly to cells in the gastrointestinal walls or respiratory tree, invading macrophages and triggering the generation and/or release of such inflammatory cytokines as interferon gamma, IL-2, IL-6, IL-12, GM-CSF and TNF, which may promote HIV replication.

Most of the anti-MAC research effort is focused on prophylaxis with drugs that directly kill the organism. The Food and Drug Administration has approved both rifabutin and clarithromycin (the latter just at the end of last year) for the primary prevention of MAC, as placebo-controlled studies have shown a reduction in the rates of MAC bacteremia and symptoms related to MAC disease.

Clarithromycin vs. Rifabutin

At the Third Conference on Retroviruses and Opportunistic Infections this winter, the results of the first MAC prophylaxis study comparing clarithromycin, rifabutin and the combination of the two were presented by Connie Benson, M.D., from Rush Medical College in Chicago (abstract 205). In this phase III double-blind study, 1,216 volunteers were randomized to clarithromycin (500 mg twice daily), rifabutin (450 mg/day) or a combination of the two. The dose of rifabutin was subsequently lowered to 300 mg/day, due to an unacceptably high incidence (three percent) of uveitis (inflammation of the eye's iris and associated tissue). A second study sponsored by the National Institute of Allergy and Infectious Diseases showed that there was a drug-drug interaction resulting in higher plasma levels of rifabutin when clarithromycin was administered concomitantly.

The results of the comparative study found rates of MAC disease to be nine percent in the clarithromycin arm, fifteen percent in the rifabutin arm and seven percent in the combination arm, a highly significant difference in favor of the clarithromycin-containing arms. The death rates were similar in all three arms. The percentage of patients requiring treatment discontinuation was higher in the combination arm (31 percent) than in either monotherapy arm (sixteen percent for clarithromycin and nineteen percent for rifabutin). The most common side effects were nausea and vomiting, diarrhea, abdominal pain, anemia, neutropenia, thrombocytopenia and elevation of alkaline phosphatase blood levels (indicative of liver inflammation).

Preliminary drug susceptibility analysis for isolates recovered from patients who developed MAC bacteremia during the study indicates that 27 percent, zero percent and 24 percent of isolates from patients assigned to clarithromycin, rifabutin or the combination, respectively, were definitely resistant to clarithromycin. In the same three arms, only four percent, two percent and none of the isolates, respectively, were resistant to rifabutin.

The researchers concluded that clarithromycin alone was more effective than rifabutin alone in reducing the incidence and delaying the time to development of MAC disease. Clarithromycin alone also was as effective as the combination but less toxic. Finally, the use of rifabutin alone did not appear to select for rifabutin resistance while the use of clarithromycin did appear to promote clarithromycin resistance. Combining both drugs did not significantly reduce the rate of clarithromycin resistance.

The true impact of clarithromycin resistance is not clearly understood. Clarithromycin's manufacturer Abbott Laboratories found in a previous prophylaxis trial that those patients who developed clarithromycin-resistant MAC while on clarithromycin had the same survival time as those who developed MAC on placebo. But resistance to clarithromycin creates azithromycin resistance, too. This cross-resistance severely limits a patient's treatment options. A number of studies have shown that effective treatment of disseminated MAC requires a combination of drugs that includes one of these two "macrolide" antibiotics.

Azithromycin Once a Week

A study involving prophylactic azithromycin was also presented at the Third Conference on Retroviruses and Opportunistic Infections (abstract 204). It was conducted by Diane Havlir, M.D., and her colleagues from the University of California San Diego and sponsored by Pfizer, maker of azithromycin. In this study, 669 persons with CD4 counts less than 100 were randomized to receive either azithromycin (1,200 mg once weekly), rifabutin (300 mg/day) or the combination (using the same doses). The rates of MAC disease were 15.3 percent in the rifabutin arm, 7.6 percent in the azithromycin arm and 2.7 percent in the combination arm -- a significant difference favoring the combination. There were no differences in survival or dose-limiting toxicities, although the incidence of side effects (mostly gastrointestinal) was highest in the combination arm (22.7 percent). Half of the volunteers receiving azithromycin had diarrhea at least once, but only 3.8 percent of those taking the drug had to discontinue it.

Only two of eighteen (eleven percent) of the MAC isolates obtained from patients in the azithromycin arm were resistant to both azithromycin and clarithromycin. None of the five isolates from the combination arm had resistance to macrolide antibiotics.

This study found that the azithromycin/rifabutin regimen was associated with the lowest rate of MAC breakthrough. The rates of other bacterial infections in this study were similar among the three groups. In contrast, another Pfizer-sponsored, placebo-controlled study of once weekly azithromycin (1,200 mg/week) in patients with CD4 counts below 100 found that azithromycin also protected against other bacterial infections (abstract 203). MAC breakthrough rates in this study were 8.2 percent with azithromycin and 23.3 percent with placebo. Eighty-three percent of the volunteers on azithromycin reported gastrointestinal side effects compared to 44 percent of the patients on placebo. Only 8.2 percent discontinued azithromycin treatment due to toxicity, compared to 2.3 percent of the placebo group.

Clarithromycin and azithromycin are closely related drugs, with similar anti-MAC activity and toxicity. What sets the two apart is their durability in the blood and cells and hence their dosing regimens. Once weekly azithromycin may be both cheaper and more convenient than twice daily clarithromycin. Without a head-to-head clinical trial, though, it is hard to determine whether one regimen is more effective or less toxic than the other, although it is unlikely that this trial will occur. Pfizer anticipates FDA approval in mid-May for azithromycin at the 1,200 mg once weekly dose. The price is expected to be about $1,000 a year.

Deciding on Prophylaxis

The overall conclusion from these MAC prophylaxis trials is that either clarithromycin (500 mg twice daily) or azithromycin (1,200 mg once a week) are the most effective regimens, with a potential survival benefit reported for clarithromycin in an earlier study.2 Yet those with breakthrough MAC while on either of these macrolide antibiotics have a relatively high rate of MAC resistant to both drugs.

Rifabutin is less effective in preventing MAC, but breakthrough isolates have lower rates of resistance. Rifabutin also interacts with many other common drugs used in HIV disease, including protease inhibitors (saquinavir and ritonavir). It can lower other drugs' blood levels, thus decreasing their effectiveness.

MAC prophylaxis is now recommended for patients with CD4 counts below 75. Many clinicians keep patients on prophylaxis even if their counts climb above this threshold due to protease inhibitors or other drugs. Whether effective anti-HIV therapy can make MAC prophylaxis superfluous is one of the great unanswered questions.

1 von Reyn CF et al., Lancet. May 7, 1994; 343(8906): 1137-41.

2 Pierce M et al. Tenth International Conference on AIDS. Aug. 7-12, 1994; 10(2):70(abstract 558B).

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