Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 6: Disease-Specific Treatment

Mycobacterium avium Complex

Background

Mycobacterium avium complex (MAC) is an opportunistic infection caused by species of Mycobacterium that can cause severe illness in people with advanced AIDS but rarely affects others. The risk of disseminated MAC (DMAC) is directly related to the severity of immunosuppression. DMAC typically occurs in persons with CD4 counts of <50 cells/µL, and its frequency increases as the CD4 count declines. In the absence of antibiotic prophylaxis, DMAC occurs in up to 40% of AIDS patients with CD4 counts of <50 cells/µL. Antimicrobial therapy, especially if given in conjunction with antiretroviral therapy (ART) that achieves immune reconstitution, can be successful in treating MAC disease. Specific antimicrobial prophylaxis and effective ART may also be used to prevent MAC in patients with advanced AIDS (see chapter Preventing Exposure to Opportunistic and Other Infections).

Mycobacterium organisms are common in the environment. They are found worldwide and have been isolated from soil, water, animals, birds, and foods. They usually enter the body through the respiratory or gastrointestinal tract and disseminate to cause multisystem infection, typically manifested by nonspecific symptoms and signs such as fever, sweats, weight loss, abdominal pain, fatigue, chronic diarrhea, and anemia and other cytopenias. MAC can also cause local disease such as central nervous system infection, soft-tissue or bone infections, or endocarditis. In patients with subclinical or incompletely treated MAC who have recently started ART, an immune reconstitution inflammatory syndrome may occur with localized lymphadenitis or paradoxically worsening symptoms may (see chapter Immune Reconstitution Syndrome).

S: Subjective

The patient complains of 1 or more of the following symptoms:

• Persistent or cyclic fever
• Night sweats
• Unintentional weight loss
• Anorexia
• Chronic diarrhea
• Weakness
• Fatigue
• Abdominal pain

During the history, ask about the following:

• Any symptoms as above, including duration and intensity; other symptoms of infection
• Whether the patient is taking MAC prophylaxis or ART

O: Objective

Perform a full physical examination with particular attention to the following:

• Vital signs (temperature, heart rate, blood pressure, respiratory rate)
• Weight (compare with previous measurements)
• General appearance (cachexia, wasting, signs of chronic illness, jaundice, pallor)
• Lymph nodes (lymphadenopathy)
• Abdomen (hepatosplenomegaly, tenderness)

Review previous laboratory values, particularly the CD4 cell count (usually <50 cells/µL).

A: Assessment

Rule out other infectious or neoplastic causes of constitutional symptoms, anemia, or organomegaly. A partial differential diagnosis would include the following:

• Mycobacterium tuberculosis
• Cytomegalovirus
• Lymphoma
• Bartonella
• Disseminated fungal infection
• Pyogenic abscess
• Other septicemia

P: Plan

Diagnostic Evaluation

A definitive diagnosis requires isolation of MAC from the blood or other normally sterile body fluids or tissues (M avium cultured from sputum, bronchial washing, or stool may represent colonization rather than infection). Send blood for acid-fast bacilli (AFB) culture (2-3 samples drawn at different times will increase sensitivity).

Because MAC may take weeks to grow in culture, ancillary studies should be performed. These are not specific, but may be helpful in reaching a presumptive diagnosis:

• Complete blood count (CBC) for anemia, lymphopenia, thrombocytopenia
• Serum alkaline phosphatase (often elevated in DMAC)
• Computed tomography (CT) scan of the chest and abdomen (intra-abdominal and mediastinal lymphadenopathy or hepatosplenomegaly are often present)

If blood cultures are negative and MAC is suspected, consider biopsy of the lymph nodes, bone marrow, liver, or bowel (via endoscopy) to detect DMAC by microscopic examination for AFB and culture. If the evidence suggests pulmonary MAC, consider bronchoscopy and bronchoalveolar lavage.

Perform additional studies as indicated to rule out other causes of the patient's symptoms, including bacterial blood cultures, sputum for M tuberculosis, Bartonella studies, lymph node cytology for lymphoma, and stool cultures.

Treatment

Because antimicrobial resistance develops quickly with single-drug therapy, multidrug regimens must be administered for DMAC.

The U.S. Centers for Disease Control and Prevention recommends the following 2-drug regimens:

• Clarithromycin 500 mg twice daily + ethambutol 15 mg/kg once daily
• Azithromycin 500-600 mg once daily + ethambutol 15 mg/kg once daily

Some experts recommend including a third agent for more advanced disease or for patients not taking effective ART. The addition of rifabutin (300 mg daily) has been associated with increased mycobacterial clearance, but no survival benefit. A fluoroquinolone (eg, ciprofloxacin, levofloxacin) or amikacin may be used instead of rifabutin as a third agent, or in addition to rifabutin as a fourth agent; however, studies have not confirmed the clinical benefit of these medications.

Because immune reconstitution is essential for controlling MAC, all patients not already taking ART should begin ART, if possible. Patients taking suboptimal ART should be evaluated for enhancement of their regimen. The optimal timing of ART initiation in relation to MAC treatment is unclear. Because immune reconstitution from effective ART may cause a paradoxical inflammatory response if started during active DMAC infection, some experts recommend treating DMAC for about a month before adding antiretroviral (ARV) medications (see chapter Immune Reconstitution Syndrome). This strategy also helps to avoid or forestall interactions between DMAC and ARV drugs and the additive toxicities of these medications.

Clarithromycin is often considered the macrolide of choice for use in combination therapy for MAC, but azithromycin is equally efficacious and may cause fewer gastrointestinal adverse effects and drug interactions. In particular, clarithromycin should not be combined with efavirenz because the interaction will result in decreased efavirenz drug concentrations.

Rifabutin has significant interactions with many drugs, including ARV medications and therefore dosage adjustments or alternative agents may be needed (Table 1).

Table 1. Interactions between Rifabutin and Antiretroviral Medications: Contraindicated Combinations and Dosage Adjustments

Antiretroviral Agent Management When Used with Rifabutin Nonnucleoside Reverse Transcriptase Inhibitors Efavirenz Use standard efavirenz dosage; increase rifabutin to 450-600 mg daily. Nevirapine Use standard dosage of nevirapine; give rifabutin at 300 mg daily or 3 times weekly. Delavirdine Do not combine. Ritonavir-Boosted Protease Inhibitors Lopinavir/Ritonavir (Kaletra) Give standard dosage of lopinavir/ritonavir; decrease rifabutin to 150 mg alternate days or 3 times weekly. All Other Ritonavir-Boosted PIs Give standard dosage of PI/ritonavir; decrease rifabutin to 150 mg on alternate days or 3 times weekly. Unboosted Protease Inhibitors Ritonavir Use ritonavir at standard dosage; give rifabutin at 150 mg on alternate days or 3 times weekly. Amprenavir, Fosamprenavir Use PIs at standard dosages; give rifabutin at 150 mg/day or 300 mg 3 times weekly. Atazanavir Give atazanavir at standard dosage; give rifabutin at 150 mg on alternate days or 3 times weekly. Indinavir Increase indinavir to 1,000 mg every 8 hours; give rifabutin at 150 mg/day or 300 mg 3 times weekly. Nelfinavir Increase nelfinavir to 1,000 mg every 8 hours; give rifabutin at 150 mg/day or 300 mg 3 times weekly. Ritonavir Give ritonavir at standard dosage; give rifabutin at 150 mg on alternate days or 3 times weekly.

Source: HIV InSite. Database of Antiretroviral Drug Interactions. San Francisco: UCSF Center for HIV Information. Available online at http://hivinsite.ucsf.edu/arvdb?page=ar-00-02. Accessed April 26, 2006.

The patient should show clinical improvement within the first weeks of treatment. If the patient is not responding to treatment after 2-4 weeks of therapy, assess adherence, consider adding 1 or more drugs, and consider evaluation for other or additional causes of the patient's symptoms. Consider repeating a blood culture with antimicrobial sensitivities in patients whose clinical status has not improved after 4-8 weeks of treatment. If immune reconstitution inflammatory reactions are suspected, consider adding anti-inflammatory medications (see chapter Immune Reconstitution Syndrome).

Treatment of MAC is generally required for the remainder of the patient's life, although it may be reasonable to discontinue MAC therapy if patients complete at least 12 months of MAC treatment, have no further symptoms, and demonstrate immune restoration in response to ART (an increase in CD4 counts to >100 cells/µL for at least 6 months). If MAC treatment is discontinued, the patient must be monitored carefully for any decrease in CD4 cell count or recurrence of MAC symptoms. Some clinicians verify negative AFB cultures before discontinuing therapy. Treatment should be resumed if the CD4 count drops to <100 cells/µL or if symptoms recur.

Patient Education

• Advise patients that antimycobacterial therapy alone will not eradicate MAC infection, but should decrease symptoms and improve quality of life. A response to treatment may take up to 4 weeks. If medications are discontinued, the disease almost always recurs, unless the CD4 count has increased to >50-100 cells/µL in response to ART.
• Patients must take all medicines exactly as prescribed. If doses are missed, or if the medication is stopped and restarted, Mycobacterium can develop resistance to the medications. If patients are having trouble taking the medications on schedule, they should contact their health care providers immediately.
• Educate patients about the benefits of ART in strengthening the immune system and preventing opportunistic infections such as DMAC.
• Urge patients to contact the clinic immediately if they notice worsening symptoms, or new symptoms.
• DMAC is an opportunistic infection of late-stage HIV and indicates profound immune suppression. Some patients may not respond to MAC treatment or to ART. Because this is a life-threatening disease, clinicians should discuss advance directives and durable power of attorney with patients. Referral to a social worker, mental health clinician, or chaplain experienced in such issues may facilitate this discussion.

References

• Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association/Infectious Diseases Society of America. Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents. MMWR Recomm Rep. 2004 Dec 17; 53(RR15);1-112. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=14. Accessed May 19, 2006.
• Centers for Disease Control and Prevention. Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex for adults and adolescents infected with human immunodeficiency virus. U.S. Public Health Service Task Force on Prophylaxis and Therapy for Mycobacterium avium Complex. MMWR Recomm Rep. 1993 Jun 25;42(RR-9):14-20. Available online at www.cdc.gov/mmwr/preview/mmwrhtml/00021272.htm. Accessed May 19, 2006.
• Horsburgh CR Jr., Gettings J, Alexander LN, et al. Disseminated Mycobacterium avium complex disease among patients infected with human immunodeficiency virus, 1985-2000. Clin Infect Dis. 2001 Dec 1;33(11):1938-43.
• Jacobson MA, Aberg JA. Mycobacterium avium Complex and Atypical Mycobacterial Infections in the Setting of HIV Infection. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]. San Francisco: UCSF Center for HIV Information; 2006. Accessed April 15, 2006.
• U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7. Accessed May 19, 2006.
• U.S. Public Health Service, Infectious Diseases Society of America. Guidelines for preventing opportunistic infections among HIV-infected persons--2002. MMWR Recomm Rep. 2002 Jun 14;51(RR08);1-46. Available online at aidsinfo.nih.gov/Guidelines/. Accessed May 19, 2006.