Recommendations on Prophylaxis and Therapy for Disseminated Mycobacterium avium Complex for Adults and Adolescents Infected with Human Immunodeficiency Virus

Summary

Mycobacterium avium complex (MAC) causes disseminated disease in up to 40% of patients with advanced human immunodeficiency virus (HIV) disease in the United States. A U.S. Public Health Service Task Force convened to address the prophylaxis and therapy of MAC recommends that patients with HIV infection and less than 100 CD4+ T-lymphocytes/uL be administered prophylaxis against MAC. The recommended regimen is rifabutin, 300 mg by mouth daily, for the patient's lifetime. If disseminated MAC develops, a treatment regimen containing clarithromycin or azithromycin and at least one other agent is recommended. Diagnosis, therapy, and prophylaxis for HIV-infected children follow similar guidelines.

INTRODUCTION

Mycobacterium avium complex (MAC) causes disseminated disease in up to 40% of patients with human immunodeficiency virus (HIV) in the United States, producing fever, sweats, weight loss, and anemia (1-3). Disseminated MAC characteristically affects patients with advanced HIV disease and peripheral CD4+ T-lymphocyte counts less than 100 cells/uL. Effective prevention and therapy of MAC has the potential to contribute substantially to improved quality of life and duration of survival for HIV-infected persons.

Two randomized, placebo-controlled, multicenter studies were recently conducted to study the use of rifabutin for the prevention of disseminated MAC, as defined by positive blood culture. In these studies, rifabutin was shown to reduce the frequency of MAC bacteremia by approximately 50% (48 of 566 patients receiving rifabutin developed MAC, compared with 102 of 580 patients receiving placebo, p less than 0.001) (4,5).

On December 23, 1992, the Food and Drug Administration issued the first approval for a prophylactic drug targeted against MAC. Data collected in published and unpublished studies (1-3) suggest that health-care providers may utilize and their patients may benefit from recommendations for prevention and management provided by a panel of experts drawn from government agencies, universities, practicing clinicians, and the community. The U.S. Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium avium Complex was convened in Bethesda, Maryland, on December 7-8, 1992, and issued the recommendations in this report. Indications for Prophylaxis

Patients with HIV infection and less than 100 CD4+ T-lymphocytes/uL should be administered prophylaxis against MAC. Prophylaxis should be continued for the patient's lifetime unless multiple drug therapy for MAC becomes necessary because of the development of MAC disease.

Clinicians must weigh the potential benefits of MAC prophylaxis against the potential for toxicities and drug interactions, the cost, the potential to produce resistance in a community with a high rate of tuberculosis, and the possibility that the addition of another drug to the medical regimen may adversely affect patients' compliance with treatment. Because of these concerns, therefore, in some situations rifabutin prophylaxis should not be administered.

Evaluation before Beginning Prophylaxis

Before prophylaxis is administered, patients should be assessed to ensure that they do not have active disease due to MAC, M. tuberculosis, or any other mycobacterial species. This assessment may include a chest radiograph and tuberculin skin test. Prophylactic Regimens

Rifabutin, 300 mg by mouth daily, is recommended for the patient's lifetime unless disseminated MAC develops, which would then require multiple drug therapy (4,5). Although other drugs, such as azithromycin and clarithromycin, have laboratory and clinical activity against MAC, none has been shown in a prospective, controlled trial to be effective and safe for prophylaxis. Thus, in the absence of data, no other regimen can be recommended at this time.

The 300-mg dose of rifabutin has been well tolerated (4,5). Adverse effects included neutropenia, thrombocytopenia, rash, and gastrointestinal disturbances.

Diagnosis of MAC

Disseminated MAC is most readily diagnosed by one positive blood culture (6). Blood cultures should be performed in patients with symptoms, signs, or laboratory abnormalities compatible with mycobacterium infection. Blood cultures are not routinely recommended for asymptomatic persons, even for those who have CD4+ T-lymphocyte counts less than 100 cells/uL.

Therapy of Disseminated MAC

Although studies have not yet identified an optimal regimen or confirmed that any therapeutic regimen produces sustained clinical benefit for patients with disseminated MAC, the Task Force concluded that the available information indicated the need for treatment of disseminated MAC (7-14). The Public Health Service therefore recommends that regimens be based on the following principles:

Treatment regimens outside a clinical trial should include at least two agents.

Every regimen should contain either azithromycin or clarithromycin; many experts prefer ethambutol as a second drug. Many clinicians have added one or more of the following as second, third, or fourth agents: clofazimine, rifabutin, rifampin, ciprofloxacin, and in some situations amikacin. Isoniazid and pyrazinamide are not effective for the therapy of MAC.

Therapy should continue for the lifetime of the patient if clinical and microbiologic improvement is observed. Monitoring Patients Receiving Therapy for Disseminated MAC

Clinical manifestations of disseminated MAC -- such as fever, weight loss, and night sweats -- should be monitored several times during the initial weeks of therapy. Microbiologic response, as assessed by blood culture every 4 weeks during initial therapy, can also be helpful in interpreting the efficacy of a therapeutic regimen.

Most patients who ultimately respond show substantial clinical improvement in the first 4-6 weeks of therapy. Elimination of the organisms from blood cultures may take somewhat longer, often requiring 4-12 weeks.

Recommendations for HIV-Infected Children

HIV-infected children less than 12 years of age also develop disseminated MAC. Some age adjustment is necessary when clinicians interpret CD4+ T-lymphocyte counts in children less than 2 years of age. Diagnosis, therapy, and prophylaxis should follow recommendations similar to those for adolescents and adults.

References

1. Horsburgh CR. Mycobacterium avium complex infection in the

acquired immunodeficiency syndrome. N Engl J Med 1991;324:1332-8.

2. Chaisson RE, Moore RD, Richman DD, Keruly J, Creagh T, the Zidovudine Epidemiology Study Group. Incidence and natural history of Mycobacterium avium complex infection in patients with advanced HIV disease treated with zidovudine. Am Rev Respir Dis 1992;146:285-9.

3. Havlik JA, Horsburgh CR, Metchock B, Williams P, Fann SA, Thompson SE. Disseminated Mycobacterium avium complex infection: clinical identification and epidemiologic trends. J Infect Dis 1992;165:577-80.

4. Gordin F, Nightingale S, Wynne B, et al. Rifabutin monotherapy prevents or delays Mycobacterium avium complex bacteremia in patients with AIDS (abstract no. B100). In: Program and Abstracts of the VIII International Conference on AIDS/Third STD World Congress (Amsterdam). Amsterdam: Harvard University/Dutch Foundation, 1992.

5. Cameron W, Sparti P, Pietroski N, et al. Rifabutin therapy for the prevention of M. avium complex bacteremia in patients with AIDS and CD4 less than 200 (abstract no. We54). In: Program and Abstracts of the VIII International Conference on AIDS/Third STD World Congress (Amsterdam). Amsterdam: Harvard University/Dutch Foundation, 1992.

6. Evans KD, Nakasome AS, Sutherland PA, de la Maza LM, Peterson EM. Identification of Mycobacterium tuberculosis and Mycobacterium avium-M. intracellulare directly from primary BactecR cultures by using acridinium-ester labeled DNA probes. J Clin Microbiol 1992;30:2427-31.

7. Kemper C, Havlir D, Haghighat D, et al. Effect of ethambutol, rifampin, or clofazimine, given singly, on Mycobacterium avium bacteremia in AIDS. VIII International Conference on AIDS: Amsterdam, The Netherlands, July 19-24, 1992:PoB 3087.

8. Chaisson RE, Benson CA, Dube M, et al. Clarithromycin therapy for disseminated Mycobacterium avium-complex (MAC) in AIDS. Abstracts of the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy, Anaheim, California, 1992;89l.

9. Dautzenberg B, Truffot C, Legris S, et al. Activity of clarithromycin against Mycobacterium avium infection in patients with the acquired immune deficiency syndrome: a controlled clinical trial. Am Rev Respir Dis 1992;144:564-9. 10. Young LS, Wiviott L, Wu M, Kolononski P, Bolan R, Inderlied CB. Azithromycin for treatment of Mycobacterium avium-intracellulare complex infection in patients with AIDS. Lancet 1991;338:1107-9. 11. Kemper CA, Meng TC, Nussbaum J, et al. Treatment of Mycobacterium avium complex bacteremia in AIDS with a four-drug oral regimen: rifampin, ethambutol, clofazimine and ciprofloxacin. Ann Intern Med 1992;116:466-72. 12. Agins BD, Berman DS, Spicehandler D, El-Sadr W, Simberkoff MS, Rahal J. Effect of combined therapy with ansamycin, clofazimine, ethambutol, and isoniazid for Mycobacterium avium infection in patients with AIDS. J Infect Dis 1989;159:784-787. 13. Hoy J, Mijch A, Sandland M, Grayson L, Lucas R, Dwyer B. Quadruple-drug therapy for Mycobacterium avium bacteremia in AIDS patients. J Infect Dis 1990;161:801-5. 14. Horsburgh CR, Havlik JA, Metchock BG, Thompson SE. Oral therapy of disseminated Mycobacterium avium complex infection in AIDS relieves symptoms and is well tolerated. Am Rev Respir Dis 1991;143:A115.

SUGGESTED CITATION: Centers for Disease Control and Prevention. Recommendations for counseling persons infected with human T-lymphotropic virus, types I and II. Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex for adults and adolescents infected with human immunodeficiency virus. MMWR 1993;(No. RR- 9):{inclusive page numbers}.

CIO Responsible for this publication: National Center for Infectious Disease,

Division of HIV/AIDS Division of Viral and Rickettsial Diseases

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