Special Report
Recommendations on Prophylaxis and Therapy for Disseminated Mycobacterium avium Complex Disease in Patients Infected with the Human Immunodeficiency Virus
N Engl J Med 1993; 329:898-904September 16, 1993
- Article
Mycobacterium avium complex causes disseminated disease in as many as 15 to 40 percent of patients with human immunodeficiency virus (HIV) infection in the United States, causing fever, night sweats, weight loss, and anemia1-7. Disseminated M. avium complex disease characteristically occurs in patients with very advanced HIV disease and peripheral-blood CD4 T-lymphocyte counts below 100 cells per cubic millimeter. Effective prevention and therapy of M. avium complex infection would probably improve the quality and duration of survival for HIV-infected persons.
During the first decade of the HIV pandemic in the United States, health care providers recognized that M. avium complex could cause disseminated disease and described microbiologic and histopathologic evidence of organ involvement at autopsy. Clinicians generally focused little attention on M. avium complex, because most available drugs appeared to have little in vitro activity, and published trials reported disappointing therapeutic results. During the past five years, however, several newer antimicrobial agents with activity against M. avium complex have become available. On December 23, 1992, the Food and Drug Administration (FDA) issued the first approval for a drug (rifabutin) targeted against M. avium complex. This milestone, along with data collected in an increasing number of studies, suggests that health care providers and their patients may benefit from recommendations for prevention and management.
Background
Epidemiology
M. avium complex infection received little attention before the HIV epidemic because it infrequently caused disease in humans. Most cases involved either pulmonary infections in immunologically normal persons with chronic lung disease or cervical adenitis in children. Disseminated disease was rare, even among severely immunosuppressed persons, but for unexplained reasons HIV seems to predispose people in a unique fashion to the development of disseminated M. avium complex disease2,8.
M. avium complex is ubiquitous in the environment and can be recovered from fresh water, sea water, soil, and dairy products, as well as from a wide variety of animals, including chickens, pigs, dogs, cats, and insects4,5,9. The environmental sources that contribute to infection and disease in humans are not clear, since isolates from local environmental sources often differ substantially from local human isolates with regard to serotype and plasmid profile. Both the respiratory and the gastrointestinal tract have been proposed as portals of entry for M. avium complex. The gastrointestinal tract is thought to be the most common site of colonization and dissemination10-12.
Clinical Manifestations
Localized disease caused by M. avium complex includes cervical adenitis, pneumonitis, hepatic dysfunction, skin lesions, endophthalmitis, and abscesses. Patients with localized disease have somewhat higher CD4 T-lymphocyte counts than those with disseminated disease. It is logical to assume that patients with localized disease and perhaps those who are colonized are at high risk for disseminated disease, although this has not been clearly established12.
Disseminated M. avium complex disease may appear as fever, weight loss, night sweats, diarrhea, abdominal pain, anemia, or an elevated serum concentration of alkaline phosphatase1-4. Patients often have intraabdominal lymphadenopathy and hepatosplenomegaly. These symptoms, signs, and laboratory abnormalities are nonspecific, however, and may be caused by a variety of infectious and neoplastic processes. Although M. avium complex may be a marker for severe immunosuppression in patients whose fever or inanition is caused by another process, case-control studies have demonstrated that M. avium complex can cause systemic symptoms, especially in patients with bacteremia. Therapeutic trials correlating reduction in bacteremia with improvement in symptoms also support M. avium complex as a cause of morbidity.
The principal predictor of an increased risk of M. avium complex disease is the peripheral-blood CD4 T-lymphocyte count1,3,4,6,7. In several published series, the median count in adult patients with disseminated disease ranged from 10 to 50 cells per cubic millimeter, with very few patients having counts higher than 100 cells per cubic millimeter1,4,6,7,10,11. Additional factors correlating with the development of disseminated M. avium complex disease include the time since the diagnosis of AIDS, the presence of substantial anemia (hemoglobin level, <8 g per deciliter), previous opportunistic infection, and any interruption in zidovudine therapy1,7.
No prospective study has precisely defined the effect of untreated disseminated M. avium complex disease on prognosis, but several cohort and case-control studies suggest that this entity is associated with reduced survival (Figure 1Figure 1
Survival of Patients with Untreated Disseminated M. avium Complex Infection (Double Line) and Matched Control Patients without Such Infection (Single Line).)1,13. One study suggested that the median survival among patients with untreated disseminated M. avium complex disease was 4 months, as compared with 11 months among patients without disseminated M. avium complex13. Another study calculated the median survival in these two groups as 3.5 and 9.1 months, respectively6. A prospective cohort study of more than 1000 patients with advanced HIV disease showed that patients in whom M. avium complex disease developed had a significantly increased risk of death, even when other predictors of mortality were controlled for1. Although such studies clearly indicate an association between disseminated M. avium complex disease and reduced survival, they do not conclusively attribute the mortality to M. avium complex.Prophylaxis
Prevention of disseminated M. avium complex disease is an important goal in the management of HIV infection and low CD4 T-lymphocyte counts, since disseminated M. avium complex disease occurs so frequently and appears to increase morbidity. Rifabutin has good in vitro activity against M. avium complex, and although this does not necessarily correlate with in vivo activity, the drug has moderate activity in some animal models of disseminated M. avium complex disease. To date, rifabutin is the only drug to have been analyzed in a large, prospective, completed prophylactic trial. The results of that trial are reported in this issue of the Journal14.
A total of 1146 patients were enrolled in two similar studies: 566 received rifabutin (300 mg per day taken orally), and 580 received placebo. In an intention-to-treat analysis, M. avium complex disease developed in 102 patients assigned to placebo, as compared with only 48 patients assigned to rifabutin (P<0.001). The relative risks for the development of mycobacteremia in the placebo recipients as compared with the rifabutin recipients were 2.3 (95 percent confidence interval, 1.4 to 3.8) and 2.1 (95 percent confidence interval, 1.3 to 3.4) in the two studies. When only the patients in whom M. avium complex disease developed during the double-blind phase of the analysis were evaluated, it was found to have developed in 89 patients receiving placebo, as compared with 35 patients receiving rifabutin (P<0.001). Relative risks by this analysis were 3.1 (95 percent confidence interval, 1.6 to 5.8) and 2.4 (95 percent confidence interval, 1.4 to 4.4) in the two studies. Overall, there was no survival difference between the two groups, but these studies were not designed to show such differences.
In these studies, rifabutin reduced the frequency of M. avium complex bacteremia by about half during the course of treatment (mean, 218 days). The benefit was almost entirely limited to those with CD4 counts below 75 cells per cubic millimeter at entry, and there was no benefit in those with counts above 100 cells per cubic millimeter at entry. However, linking rifabutin therapy to a clinical benefit was difficult because of the relatively short duration of the trial and the rate of background events due to other opportunistic infections in this very immunosuppressed population. Retrospective analyses conducted by the FDA review staff which examined the contemporaneous occurrence of M. avium complex bacteremia and clinical indicators of M. avium complex disease (fever, weight loss, anemia, elevated serum alkaline phosphatase, and elevated serum aminotransferases) in the two study groups convinced the reviewers, the FDA's Advisory Panel on Antiviral Drugs, and this Task Force that rifabutin prophylaxis produced substantial clinical benefit. The duration of clinical or microbiologic benefit could not be established, since the trial had been terminated. The overall rate of reported adverse events did not differ significantly between the patients receiving rifabutin and those receiving placebo, although twice as many patients in the rifabutin group discontinued the drug because of apparent toxicity (16 percent) as in the placebo group (8 percent). Neutropenia was associated with the administration of rifabutin. Other reports have recognized thrombocytopenia, nausea, flatulence, hepatitis, and rash as adverse reactions to rifabutin.
Susceptibility testing was performed on 59 isolates of M. avium complex from patients receiving placebo and on 29 isolates from patients receiving rifabutin. Unexpectedly, no difference was observed in the distribution of minimal inhibitory concentrations in the two groups, with approximately one quarter of the isolates having a minimal inhibitory concentration of 0.5 μg per milliliter or less. Thus, when bacteremias occurred during rifabutin prophylaxis, prophylaxis did not appear to select isolates with increased resistance. Rifabutin increases the hepatic metabolism of certain drugs; the area under the curve of the serum zidovudine concentration, plotted against time, is decreased by 20 to 25 percent in patients receiving rifabutin. Thus, health care professionals need to be cognizant of the potential for drug interactions.
Diagnosis and Susceptibility Testing
A single positive blood culture is considered diagnostic for disseminated M. avium complex disease. At very low levels of bacteremia, cultures may fluctuate between positive and negative; in most patients with such cultures, sustained, high-level bacteremia will probably develop. Many experts consider a positive culture from certain other normally sterile sites (e.g., bone marrow and liver) to have the same implication as a positive blood culture. There is some evidence that a positive acid-fast smear of stool is indicative of disseminated M. avium complex disease (presuming that the isolate is ultimately identified as M. avium complex). However, the predictive value of a negative acid-fast stool smear or a positive stool culture is poor and mitigates against the routine use of stool smears and cultures12.
Mycobacteria can be detected in blood by the inoculation of unprocessed blood or processed blood (blood concentrated by centrifugation after treatment with an agent to lyse erythrocytes and perhaps also release mycobacteria from phagocytic cells) into appropriate mediums. To obtain a suitable sample for processing, the usual procedure is to collect blood (usually 10 ml) in a tube containing an anticoagulant agent (e.g., sodium polyanetholesulfonate) or in an Isolator tube (containing lytic and anticoagulant agents) (Wampole Laboratories, Cranbury, N.J.)15,16. There is no loss of viability when mycobacteria are held in these systems for as long as seven days15. The processed sediment can be inoculated onto Middlebrook 7H10 or 7H11 agar, into Bactec 12B broth medium, or both.
In the case of unprocessed blood, 5 ml of sample can be inoculated directly into Bactec 13A or other suitable broth, avoiding the tedious procedure of lysis and centrifugation. However, this technique precludes quantitative measurement of the mycobacteremia. The possibility of carryover of drugs from the blood sample into the Bactec 13A medium, resulting in false negative cultures, is a concern that needs investigation.
M. avium complex is commonly detected with the Bactec system in 7 to 14 days, whereas its detection on agar plates usually takes 14 to 21 days. M. avium complex can be identified within hours by DNA probes (AccuProbe and Gen-Probe, San Diego, Calif.) when there is sufficient growth of M. avium complex on agar or in broth17. Sequential quantitative blood cultures on agar plates are useful in evaluating a drug's therapeutic effectiveness in clinical trials,16 but until the value of this technique is delineated for routine clinical practice, such cultures are not necessary for the management of M. avium complex infections.
A correlation between minimal inhibitory concentrations and the microbiologic response to therapy was established in a clinical trial of clarithromycin monotherapy for disseminated M. avium complex disease (AIDS Clinical Trials Group 157/Abbott M90-500)18-20. More than 90 percent of the patients had a convincing decrease in bacteremia, with most patients becoming culture-negative when their initial M. avium complex isolates had minimal inhibitory concentrations of clarithromycin of 2.0 μg per milliliter or less with the Bactec susceptibility-test system. Conversely, patients had both a clinical and a microbiologic relapse when the minimal inhibitory concentrations increased to 32 μg per milliliter or higher. On the basis of these and other data, M. avium complex strains can be tentatively classified as “susceptible” to clarithromycin if the minimal inhibitory concentration is 2 μg per milliliter or less and “resistant” to clarithromycin if the minimal inhibitory concentration is 32 μg per milliliter or more when measured in broth or agar at pH 7.4. At present, the clinical implications of minimal inhibitory concentrations between 4 and 16 μg per milliliter are unclear, since concentrations in this range may reflect either methodologic or microbial variability. There is no published evidence that any currently available methods of susceptibility testing using drugs other than the macrolides are of value in guiding or modifying therapeutic regimens. Some centers with extensive experience believe it is reasonable to presume that a clinical response will be unlikely if the minimal inhibitory concentration for the patient's isolate exceeds achievable plasma or tissue levels21.
Therapy of Disseminated M. avium Complex Disease
The goal of therapy for disseminated M. avium complex disease is to reduce the amount of mycobacteria in patients or to eradicate it from patients altogether and thereby improve the quality or duration of their survival. Studies to date have documented that certain individual drugs19,21-23 and regimens of multiple drugs23-30 can reduce or eliminate M. avium complex bacteremia over several weeks or months. It is currently unknown, however, how such therapy affects the total tissue burden of M. avium complex and whether patients benefit clinically and microbiologically for extended periods.
Single-agent therapy of disseminated M. avium complex disease has been studied with clarithromycin,19-21 azithromycin,22 ethambutol,23 clofazimine,23 rifampin,23 and the experimental quinolone sparfloxacin. Clarithromycin, azithromycin, and ethambutol demonstrated microbiologic activity in clinical trials of short duration when used as single agents. Efficacy was documented by the presence of reduced numbers of M. avium complex colony-forming units in the blood after four to six weeks of therapy. In many patients with reductions in M. avium complex bacteremia there was also considerable resolution of fever and weight loss. However, the condition of a substantial number of these patients subsequently deteriorated, with recurrence of symptoms and an increasing quantity of circulating M. avium complex. This occurred both in patients who discontinued anti-M. avium complex therapy and in those who continued single-drug therapy. Figure 2Figure 2
Mean (±SE) Concentrations of M. avium Complex in the Blood of 16 Patients during and after 35 Days of Treatment with Azithromycin. shows the number of colony-forming units of M. avium complex detected in a cohort of patients receiving azithromycin monotherapy (500 mg orally each day) for 35 days, after which some patients continued therapy and others did not22. Similar results are obtained when patients are treated with clarithromycin (0.5 to 1.0 g orally two times a day)19,21. This suggests that monotherapy with these agents at these doses does not eradicate M. avium complex and that resistance can develop.Although clinical trials support the in vivo microbiologic activity of clarithromycin, azithromycin, and ethambutol, resistance to antibiotics develops when azithromycin or clarithromycin is used for monotherapy. Agents such as clofazimine, rifampin, and sparfloxacin, which have in vitro activity but failed to reduce M. avium complex bacteremia when used as single agents, may prove useful if higher doses, longer courses, or synergistic drug combinations are used.
For tuberculosis, multiple drug therapy has been the standard approach to treatment. The precedents established for M. tuberculosis therapy are likely to be pertinent to therapy for M. avium complex. M. tuberculosis spontaneously develops mutants resistant to various chemotherapeutic agents at a rate of 1 organism in 1 million to 1 billion. When the total body burden of M. tuberculosis is low, this mutation rate is not important. When there are enormous populations of organisms -- i.e., 1 billion to 100 billion organisms in pulmonary cavities -- a relatively large number of resistant organisms will be present initially. Under the selective pressure of single-drug therapy, the resistant organisms will continue to proliferate and repopulate the cavity, organ, or tissue. With two-drug therapy, the likelihood that one isolate will be resistant to both drugs is substantially lower, representing the product of two frequencies. Thus, regimens of two or three drugs are more likely to provide a sustained response.
The same phenomenon is expected to occur with disseminated M. avium complex, especially in immunocompromised patients with AIDS. Because the burden of M. avium complex organisms in the body may exceed 1 billion, therapy with two or more drugs is likely to be needed to treat disseminated infections24-31. The microbiologic results of two published trials of combination therapy are shown in Table 1Table 1
Microbiologic Efficacy of Two Types of Combination Therapy for M. avium Complex Infection. 24,28 . Microbiologic improvement was documented on the basis of the decline in mycobacteremia. Many patients who had substantial reductions in bacteremia also had clinical benefit, as manifested by reduction in fever, increase in weight, or improvement in subjective sense of well-being. The results of these trials are difficult to compare, however, since different methods of data collection and analysis were used. In addition, sicker patients with poor responses to treatment tended to leave the studies in succeeding weeks, biasing the data collected later in favor of the patients with better responses who remained in the study. These findings thus suggest, but do not prove, that multiple drug regimens can have microbiologic and clinical benefit.One of the problems of a multiple-drug approach to treat M. avium complex infection is drug toxicity. Each agent is associated with a toxic effect, and some effects are overlapping, such as gastrointestinal intolerance (Table 2Table 2
Antimycobacterial Agents Commonly Used to Treat M. avium Complex Infection.). In a recent multidrug clinical trial, adverse reactions requiring the discontinuation of a drug to treat M. avium complex infection occurred in 46 percent of patients24. Drug interactions also occur among the multiple concomitant medications patients take. These interactions have not been carefully assessed, although some, such as the decrease caused by rifabutin in the area under the curve of the serum zidovudine concentration plotted against time, the effect of didanosine on clarithromycin absorption, and the interactions of clarithromycin and rifabutin are being evaluated to determine their clinical importance32. Also, results of a controlled clinical trial discussed before the FDA's Antiviral Drug Advisory Committee in May 1993 suggest that mortality may be higher when clarithromycin is used at a dose of 1.0 g orally twice a day than when it is used at a dose of 0.5 g orally twice a day.Agents used in the therapy of M. avium complex infection are listed in Table 2, which provides data on dosing regimens and common adverse effects.
Source Information
National Institutes of Health, Bethesda, MD 20892
Appendix
The members of the Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium avium Complex are as follows: H. Masur (chair), National Institutes of Health, Bethesda, Md.; D. Cohn, Denver Disease Control Service, Denver; M. Cynamon, Veterans Affairs Medical Center, Syracuse, N.Y.; L. Deyton, National Institutes of Health; R. Edison, Food and Drug Administration, Bethesda, Md.; R. Eisinger, National Institutes of Health; J. Ellner, Case Western Reserve University, Cleveland; J. Feinberg, Johns Hopkins University, Baltimore; M. Goldberger, Food and Drug Administration; J. Goodgame, Orlando, Fla.; F. Gordin, Veterans Affairs Medical Center, Washington, D.C.; M. Harrington, Treatment Action Group, New York; D. Havlir, University of California, San Diego; C.R. Horsburgh, Jr., Centers for Disease Control and Prevention, Atlanta; C. Inderlied, Children's Hospital, University of Southern California School of Medicine, Los Angeles; C. Kemper, Stanford University School of Medicine, Palo Alto, Calif.; J. Korvick, National Institutes of Health; L. Lewis, National Cancer Institute, Bethesda, Md.; A. Macher, Health Resources and Services Administration, Rockville, Md.; B. Petty, Johns Hopkins University; M. Polis, National Institutes of Health; F. Sattler, University of Southern California Medical Center, Los Angeles; E. Sloand, National Institutes of Health; and R. Wallace, University of Texas Health Center, Tyler. Consultants: R.E. Chaisson, Johns Hopkins University; C. Benson, Rush Medical College, Chicago; and L. Heifets, National Jewish Center for Immunology and Respiratory Medicine, Denver.
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