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Published in the
Bulletin of Experimental Treatments for AIDS December 1996 issue,
by the San Francisco AIDS Foundation.
December
1996 Table of Contents
Main Page
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Mycobacterium avium
Complex Disease: Clinical Updates
by Leslie Hanna
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
Prophylaxis
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.
Treatment
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.
What's Changed?
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.
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Cohn DL and others. A prospective, randomized, double-blind,
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rifabutin versus the combination for the prevention of Mycobacterium
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patients with CD4 counts less than or equal to 100 cells/mm3.
XI International Conference on AIDS. Vancouver, BC. July 1996. Abstract
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Page last updated 17 December 1996
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