The natural history of Mycobacterium avium complex (MAC) disease in people with HIV/AIDS is well understood. MAC is the third most common AIDS-related opportunistic infection, and the most common systemic bacterial infection in people with advanced HIV disease in the developed world. It is caused by an ubiquitous organism, Mycobacterium avium, that is widely dispersed throughout the environment (in water, soil, dust and contaminated food) and is therefore difficult to avoid. MAC occurs in 10-40% of people with AIDS. The main risk factor for developing MAC is severe immunosuppression, and it is a particular risk for people with fewer than 50 CD4 cells/mm3. Cumulative data suggest that the median CD4 cell count at the time of diagnosis is 10 CD4 cells/mm3. As antiviral treatments for HIV continue to improve and Pneumocystis carinii pneumonia (PCP) prophylaxis becomes more widely used -- leading to a decrease in PCP-related deaths -- people with HIV/AIDS are living longer, and the incidence rate of MAC appears to be on the rise. See the December 1995 issue of BETA, pages 17-24, for a comprehensive feature article on MAC disease, pathogenesis and treatment.
The research community has learned much about therapies for MAC, yet the optimal strategies for the prevention and treatment of the disease remain in question. In July 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) jointly issued recommendations for prophylaxis of various HIV-related infections, including MAC. Those recommendations are summarized below.
Standing Guidelines for Prophylaxis and Treatment of MAC
With the release of the July 1995 USPHS/IDSA guidelines on preventing opportunistic infections in people with HIV, the threshold for prophylaxis against disseminated MAC was reduced from 100 CD4 cells/mm3 (as recommended by the USPHS in 1993) to 50-75 CD4 cells/mm3. In summary, the prophylaxis guidelines state that: 1) Insufficient data exist with which to make recommendations on how to avoid exposure to MAC 2) Prophylaxis with rifabutin (Mycobutin) should be considered for HIV positive adults and adolescents with 50-75 CD4 cells/mm3 3) Blood culture results should be obtained to rule out disseminated MAC before prophylaxis is initiated 4) Active tuberculosis also should be ruled out by chest x-ray and PPD skin test before initiating rifabutin prophylaxis (since use of rifabutin may cause resistance to rifampin, a drug used to treat tuberculosis).
According to the same USPHS/IDSA recommendations, insufficient data exist on the safety and efficacy of clarithromycin (Biaxin) and azithromycin (Zithromax) in combination with rifabutin to allow recommendations about prophylaxis (a situation that has since changed, as discussed below). Screening of respiratory and gastrointestinal specimens is not recommended.
Guidelines for secondary prophylaxis recommend that people who have been treated for disseminated MAC continue to "receive full therapeutic doses for life." Prophylaxis recommendations for children include some CD4 cell threshold adjustments for children under 6 years of age.
The USPHS/IDSA recommend that at least 2 drugs be used in combination to treat MAC, including either clarithromycin or azithromycin plus ethambutol (Myambutol) as the second drug. They also recommend continuation of induction therapy for life, without alteration; in other words, induction and maintenance therapy are identical.
Although these guidelines are still in effect, the standard of care is changing, due in part to the completion of several large clinical trials. How the data and results of these trials will be incorporated into official guidelines is unclear, and research continues to provide new and useful information. Nevertheless, changes in clinical practice have already occurred.
Final results from several key studies designed to evaluate optimal antimycobacterial regimens have already provided information that is changing the way clinicians approach the prophylaxis and treatment of MAC today. Brief reviews of major studies and their results appear in the next sections of this article.
Since July 1995, clarithromycin (already an established drug for MAC treatment) has been approved as single-agent prophylaxis. Azithromycin at last has been studied and proved effective for prophylaxis, and the relative values of various prophylactic drugs are now becoming clearer. For example, rifabutin monotherapy, although never fully embraced by the treatment community, was until recently widely regarded as the sole prophylaxis option. Now, it is rapidly falling from favor. In contrast to the assertions made in the standing recommendations, issued at a time when not enough data had been gathered on the safety and efficacy of clarithromycin and azithromycin in combination with rifabutin, a study published in the August 8, 1996 New England Journal of Medicine provides evidence that these combinations are effective. In particular, combination clarithromycin/rifabutin and azithromycin/rifabutin were studied and found safe and effective for preventing MAC. C. Robert Horsburgh, Jr., MD, from Emory University, states succinctly in an editorial in the same issue of the New England Journal of Medicine, "Clarithromycin and azithromycin both have good in vitro activity against M. avium and...are effective prophylactic drugs...Either drug is more effective than rifabutin."
Change has also occurred in the treatment arena. The wisdom of combination drug treatment for disseminated MAC disease has long been recognized, since single-agent therapy quickly leads to resistance and drug failure. However, the optimal number of drugs to use in an anti-MAC cocktail has been widely debated, with some arguing in favor of theoretically high-powered combinations using 4 or 5 drugs, while others have argued that "less is more." Which drugs are best used in combination also has been controversial. Now, 2 studies of combination regimens provide compelling evidence for the use of a 3-drug regimen -- consisting of the drugs clarithromycin, ethambutol and rifabutin -- which showed both efficacy and a survival advantage when compared with a 4-drug regimen.
Finally, the association between clofazimine (Lamprene) use and increased mortality established in clinical trials has shored up a tendency to dismiss this drug as a valid candidate for use as a component in anti-MAC treatment regimens.
Prophylaxis Studies and Findings
Several studies presented at the XI International Conference on AIDS in Vancouver, BC, in July 1996, or published within the past year, have added significantly to knowledge of how to prevent MAC disease.
In Vancouver, David Cohn, MD, presented results of a study that compared 3 regimens for MAC prophylaxis: clarithromycin monotherapy, rifabutin monotherapy and combination clarithromycin/rifabutin (AIDS Clinical Trials Group 196/Community Programs for Clinical Research on AIDS 009). For a review of this study, see BETA, June 1996, page 38-39. A central finding was that clarithromycin with or without rifabutin was more effective at preventing MAC than rifabutin alone. Cohn also presented results of a study that established the safety of 1,000 mg of clarithromycin daily, in combination regimens, compared to 2,000 mg daily; the 2,000 mg dose led to increased mortality (see below).
Comparison of 2 Doses of Clarithromycin Indicates Higher Dose Increases Mortality
David Cohn, MD, and colleagues, on behalf of the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), compared the safety and efficacy of 4 regimens for treating disseminated MAC disease. From March 1995 through February 1996, people with AIDS were enrolled in the study and randomized to receive one of four 3-drug regimens. The drugs were the same, but the dose levels differed in the 4 regimens: clarithromycin (1,000 mg or 2,000 mg daily), ethambutol (800-1,200 mg daily) plus rifabutin (300 mg daily ) or clofazimine (100 mg daily). Participants were regularly monitored for clinical and microbiologic responses, toxicity, well-being, compliance, emerging drug resistance and survival. After an interim analysis in February 1996, the Data Safety and Monitoring Board recommended discontinuation of the higher dose of clarithromycin due to an unexpected increase in mortality rate among people taking that dose. At that time, those taking the higher dose began taking the lower, 1,000 mg daily dose.
When the study was presented in July in Vancouver, follow-up was still ongoing, so final analyses were not available. However, the preliminary results allow an exploration of what occurred at the 2 clarithromycin dose levels, and why the higher level was dropped in favor of the lower.
Of 85 participants enrolled early in the study, 45 were randomized to receive the lower 1,000 mg daily dose and 40 to receive the higher 2,000 mg daily dose. These 2 groups were similar in most variables: demographics, clinical profile, use of antiretrovirals and PCP prophylaxis, and entry CD4 cell count. After approximately 4.5 months, 10 people taking the lower dose and 17 people taking the higher dose had died. This constitutes 22% of the lower-dose group and 43% of the higher-dose group, a relative risk of 2.43 and a statistically significant difference. Between the 2 groups, side effects, compliance and continued use were equal. Another essentially equivalent finding between the 2 groups was that, at 2 months, clinical improvement -- such as reduction in fever and night sweats -- and microbiologic response were the same; 75% in both groups had blood sterilization, i.e., eradication of bacteria from the blood.
The conclusions follow logically enough: the higher dose of 2,000 mg clarithromycin daily was associated with an elevated death rate. The high congruence in participant characteristics in the groups makes the difference in survival rate more difficult to explain (in fact, the reasons are still unknown). Therefore, in multidrug regimens for treating disseminated MAC, daily clarithromycin doses should not exceed 1,000 mg.
Mark Pierce, MD, and others recently published results of a large placebo-controlled trial of clarithromycin for MAC prophylaxis. The randomized, double-blind study was conducted at 66 centers in the U.S. and Europe (Germany, France and the United Kingdom). All 667 participants had entry blood tests negative for MAC, 100 or fewer CD4 cells/mm3 and a life expectancy of at least 6 months. Both groups had highly similar demographic and clinical profiles (i.e., HIV-related symptoms). Participants were randomized to receive either 1,000 mg daily clarithromycin or placebo. After the first interim analysis showed that 3 times as many participants taking placebo developed MAC disease than those taking clarithromycin, the study was stopped. Follow-up continued for another 10 months, during which time 12% of participants in both arms withdrew. Those who withdrew from the treatment arm were followed for approximately 6 months longer on average.
Of the 333 participants taking active drug, 19 developed breakthrough MAC (6%). Eleven of those 19, or well over half, had bacterial strains resistant to clarithromycin. There were 107 deaths (32%) in the drug arm. In the placebo arm, 53 of 334 participants developed MAC (16%), and there were 137 deaths (41%). Throughout the study, fewer participants taking drug were hospitalized for any reason than those taking placebo (49% vs 57%). Side effects included digestive disturbances and taste alterations. Still, side effects were reportedly no more severe in the treatment arm than in the placebo arm and did not influence study withdrawal rates. Overall, participants tolerated clarithromycin well.
The researchers concluded that clarithromycin effectively prevents MAC disease and reduces mortality. They also concluded that clarithromycin effectively suppresses other common infections such as pneumonia and giardiasis, "due either to the direct effect of clarithromycin or to its ability to improve general health" by preventing disseminated MAC. Finally, they stated, "our data suggest that clarithromycin should be viewed as at least an equivalent choice [to rifabutin]" for MAC prophylaxis.
Diane Havlir, MD, and colleagues also recently published results of a large trial of MAC primary prophylaxis regimens. They enrolled 693 people with fewer than 100 CD4 cells/mm3 and blood cultures negative for MAC, and randomized them to receive either 1,200 mg weekly (i.e., taken only once per week) azithromycin, 300 mg daily rifabutin or a combination of weekly azithromycin and daily rifabutin. All 3 groups had similar demographic and clinical profiles. In an independent randomization, all participants also received either 200 mg daily or 400 mg weekly fluconazole (Diflucan).
After one year, 7.6% of those taking azithromycin, 15.3% of those taking rifabutin and 2.8% of those taking both drugs had developed MAC disease. Of those taking azithromycin who developed breakthrough MAC, 11% had strains that were resistant to the drug. No drug-resistant strains were found in those who developed MAC while taking either rifabutin or combination azithromycin/rifabutin. Interestingly, all the azithromycin-resistant isolates were also clarithromycin-resistant. Fluconazole, regardless of dose, was felt to have little impact on the MAC incidence rate.
The greatest number of side effects occurred in those taking the combination regimen, followed by those taking azithromycin monotherapy and then those taking rifabutin monotherapy. Most side effects were gastrointestinal. Still, the increased number of side effects in the combination arm did not cause more people to withdraw from the study.
During the study, other HIV-related infections or symptoms occurred with relatively equal frequency in all 3 groups, except for respiratory tract infections. Pneumonia (including PCP) and sinusitis developed in twice as many of those in the rifabutin arm as in those in the other 2 arms. Self-reported quality of life and survival were similar in all 3 groups. In conclusion, "as compared with rifabutin, azithromycin halved the risk of M. avium complex disease, [and] the combination of azithromycin and rifabutin...reduced the risk by 72% as compared with rifabutin alone." Another attractive feature of azithromycin prophylaxis is once weekly dosing. Also, in happy contrast to rifabutin, which has a large number of drug interactions, azithromycin does not interact with most other medications commonly used by people with AIDS. Rifabutin is known to interact problematically with fluconazole, itraconazole (Sporanox), methadone, AZT (Retrovir), dapsone, ketoconazole (Nizoral), clarithromycin, theophylline, and the approved protease inhibitors, saquinavir (Invirase), indinavir (Crixivan) and ritonavir (Norvir).
MAC Treatment Studies
Stephen Shafran, MD, and colleagues recently published the results of their study (also presented in Vancouver) of combination therapy for treating MAC disease. They concluded that a 3-drug combination consisting of clarithromycin, rifabutin and ethambutol is superior to the 4-drug combination they tested (rifampin, ethambutol, clofazimine and ciprofloxacin [Cipro]), which was considered the standard therapy for MAC when the study began in 1992.
The study enrolled 229 people with AIDS-related MAC, who were randomly assigned to take either the 3-drug or the 4-drug regimen. The 3-drug regimen consisted of rifabutin (300 mg daily), ethambutol (15 mg/kg daily) and clarithromycin (2,000 mg daily). This was chosen as the candidate regimen because all 3 drugs are known to have antimycobacterial efficacy. The 4-drug regimen consisted of rifampin (600 mg daily), ethambutol (15 mg/kg daily), clofazimine (100 mg daily) and ciprofloxacin (1,500 mg daily).
The mean age of the participants was 38 years. The median baseline CD4 count was 10 cells/mm3 in both groups. More people in the 4-drug group than in the 3-drug group had a history of PCP (62% vs 47%), and fewer in the 4-drug group were taking PCP prophylaxis (79% vs 93%). Discontinuation of treatment was defined as permanently stopping 2 study medications. The median times to discontinuation were 127 days for those in the 3-drug group and 68 days for those in the 4-drug group. Within 16 weeks, 2 people in the 3-drug group and 6 people in the 4-drug group discontinued use because of drug toxicities.
The results of the comparison were striking. Bacteremia (M. avium in the blood) was cleared in 69% of the people in the 3-drug group and 29% in the 4-drug group. By week four, 87% of those in the 3-drug group and 54% of those in the 4-drug group had blood sterilization, or eradication of the bacteria from the blood. Median survival was 8.6 months in the 3-drug group and 5.2 months in the 4-drug group. The most significant side effect was uveitis, a treatable inflammation of the eye, which occurred in the 3-drug group only (i.e., those taking rifabutin). After the study dose was lowered from the original 600 mg/day level to 300 mg/day, the incidence of uveitis decreased dramatically (3 of 53, compared to 23 of 63 at the 600 mg level). Otherwise, the only side effect was alteration in taste, which occurred in 9 of those taking the 3-drug combination and 1 of those taking the 4-drug combination.
This study confirmed the findings from other studies: adding other drugs to clarithromycin reduces the development of clarithromycin resistance. The relative importance of the individual drugs in the 3-drug regimen studied here could not be determined. Still, this prospective study showed that one multidrug regimen had a clear advantage over another, and that the most significant side effect, rifabutin-related uveitis, could be decreased in frequency and also could be effectively managed (by the use of steroid eyedrops). The investigators suggest in conclusion that "a regimen of rifabutin, ethambutol and clarithromycin should be considered the standard of treatment for M. avium complex infection until another regimen is found to be either more efficacious or equally efficacious with fewer toxic effects."
A very similar study by a team of French researchers, also presented in Vancouver, confirmed the findings of the Shafran trial. In this prospective trial, 134 participants with AIDS-related MAC bacteremia were randomized to receive open-label treatment with a 3-drug combination of clarithromycin (2,000 mg/day for 2 months, then 1,000 mg/day), ethambutol (1,200 mg/day) and rifabutin (450 mg/day), or a 2-drug combination with clarithromycin (same dosage) and clofazimine (200 mg/day then 100 mg/day).
All participants were evaluated at 2 and 6 months. Both groups were demographically and clinically similar. After treatment, the 2 groups were also similar in terms of MAC eradication from the blood. Death rates were also approximately equal: 25 of 67 taking the 3-drug regimen and 27 of 67 taking the 2-drug regimen died. In terms of differences between the 2 regimens, there was a significantly lower rate of relapse in the 3-drug group, the members of which were also far less likely to develop resistance to clarithromycin (3 in the 3-drug group vs 21 in the 2-drug group). Five people taking rifabutin developed uveitis, and equal numbers in both groups complained of the only other adverse reaction, gastrointestinal disturbances. The combined findings led the investigators to recommend use of the 3-drug regimen for treating MAC.
The Shafran and the French studies highlight the trend that disfavors clofazimine for MAC treatment. The study that most clearly suggested the folly of using clofazimine was presented in January 1996 at the Third Conference on Retroviruses and Opportunistic Infections in Washington, DC.
Richard Chaisson, MD, described the striking results of a controlled trial of clarithromycin plus ethambutol with or without clofazimine. In this study, 106 people with AIDS and MAC were treated with one of these 2 regimens. Those taking the 2-drug combination fared better on every score than those receiving 3 drugs, i.e., the addition of clofazimine: blood sterilization (65% vs 54%), time to negative culture (median 58 days vs 63 days), symptomatic improvement, such as reductions in fever and night sweats (87% vs 84%), and proportion of persons discontinuing because of adverse reactions (13% vs 22%).
The truly significant difference between the 2 groups concerns mortality: 38% of those taking 2 drugs died, compared to 61% of those taking 3 drugs. In the investigators' own words, "Clarithromycin/ethambutol is effective in treating MAC bacteremia and preventing resistance. The addition of clofazimine does not contribute to clinical response and is associated with higher mortality."
What Does It All Mean?
Significant advances have been made with regard to MAC prophylaxis and treatment, despite continuing uncertainties about the optimal ways to avoid MAC exposure. The new information provides additional MAC treatment options for people with advanced AIDS.
On the prophylaxis front, there are new options which decrease the risk of developing MAC disease. The current evidence of clinical and survival benefits from primary prophylaxis strongly favors preventing the development of MAC in the first place, rather than detecting and treating disease early, which represents a notable shift in thought. This understanding also makes continued research into better prevention methods more important than ever, since the prophylaxis regimens studied to date are far from ideal. For example, combination prophylaxis is more effective, yet more toxic and expensive. Rifabutin, still an important anti-MAC drug, alone or in any combination, poses problems for the many people taking protease inhibitors for HIV or any of a number of drugs that are contraindicated with rifabutin. Future studies will attempt to find strategies which allow concurrent prophylaxis against multiple opportunistic infections.
On the treatment front, the Shafran study of the 3-drug combination is the first to show a survival benefit. However, the daily dose of clarithromycin -- 2,000 mg daily -- used in Shafran's study has been associated elsewhere with decreased survival, which has led many to recommend a maximum daily dose of 1,000 mg. Important data should soon be released from a study of the independent value of rifabutin in combination therapy, data that may be very significant for those taking protease inhibitors or other contraindicated drugs.
Finally, new and better drugs are needed. Many antimycobacterial drugs that are candidates for use in combination MAC treatment (clofazimine in particular, as well as rifampin and ciprofloxacin) have already revealed their respective flaws, all of which limit their appeal for therapeutic use.
Leslie Hanna is Associate Editor of BETA.
Chaisson RE and others. Controlled trial of clarithromycin/ethambutol with or without clofazimine for Mycobacterium avium complex bacteremia in AIDS. Third Conference on Retroviruses and Opportunistic Infections. Washington, DC. January28-February 1, 1996. Abstract #LB17.
Cohn DL and others. A prospective, randomized, double-blind, comparative study of the safety and efficacy of clarithromycin versus rifabutin versus the combination for the prevention of Mycobacterium avium complex (MAC) bacteremia or disseminated MAC disease in HIV-infected patients with CD4 counts less than or equal to 100 cells/mm3. XI International Conference on AIDS. Vancouver, BC. July 1996. Abstract #WeB421.
Cohn DL and others. Comparison of 2 doses of clarithromycin in a randomized trial of 4 3-drug regimens for treatment of disseminated Mycobacterium avium complex disease in AIDS: excess mortality associated with high-dose clarithromycin. XI International Conference on AIDS. Vancouver, BC. July 1996. LB.B.6025.
Hanna L. Mycobacterium avium complex disease. BETA:17-24. December 1995.
Havlir DV and others. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. New England Journal of Medicine 335(6):392-398. August 8, 1996.
Horsburgh CR. Advances in the prevention and treatment of Mycobacterium avium disease. New England Journal of Medicine 335(6):428-429. August 8, 1996.
May T and others. The French randomized clinical trial of combination therapy with clarithromycin for MAC bacteremia in AIDS patients: final results. XI International Conference on AIDS. Vancouver, BC. July 1996. Abstract #WeB244.
Pierce M and others. A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patient with advanced acquired immunodeficiency syndrome. New England Journal of Medicine 335(6): 384-391. August 8, 1996.
Shafran SD and others. 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. New England Journal of Medicine 335(6): 377-384. August 8, 1996.
USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: a summary. Morbidity and Mortality Weekly Report 44(RR-8): 11-12. July 14, 1996. Back to the BETA Page Back to the Treatment Education and Advocacy Page Back to the San Francisco AIDS Foundation Home Page
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