1. Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected Children Mycobacterial Infections Recommendations from Centers for Disease Control and Prevention, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics

2. July 2009 2 www.aidsetc.org These slides were developed using the April 2008 Guidelines. The intended audience is clinicians involved in the care of patients with HIV. Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. Expert opinion should be sought for complex treatment regimens. – AETC NRC About This Presentation

3. July 2009 3 www.aidsetc.org Mycobacterium tuberculosis : Epidemiology  14,000 new cases of TB in United States in 2006 (6% among children <15 years of age)  1.1% of these were HIV infected  Incidence of TB in HIV-infected children 100 times higher than in uninfected  In South Africa, as many as 48% of children with TB were coinfected with HIV

4. July 2009 4 www.aidsetc.org  CD4 count is not a sufficient indicator of TB risk  Primarily infection by contact with adults in daily environment  In most cases, TB represents the progression of primary infection rather than a reactivation of disease  All confirmed and suspected TB cases should be reported to health authorities Mycobacterium tuberculosis: Epidemiology (2)

5. July 2009 5 www.aidsetc.org  BCG induced M tuberculosis has been reported in HIV-infected children vaccinated at birth  In the United States, resistance to any of the first-line anti-TB drugs occurs in 15% of children  Internationally, rate of multiple drug-resistant (MDR) TB is increasing Mycobacterium tuberculosis: Epidemiology (3)

6. July 2009 6 www.aidsetc.org  Extrapulmonary and miliary TB more common in children <4 years old  Congenital TB has been reported  Drug-resistant TB can be transmitted  Patients should be treated under assumption that drug resistance profiles of source and patient are similar Mycobacterium tuberculosis: Epidemiology (4)

7. July 2009 7 www.aidsetc.org Mycobacterium tuberculosis: Clinical Manifestations  Younger children progress more rapidly (possibly due to delayed diagnosis)  Nonspecific symptoms: fever, weight loss, failure to thrive  Pulmonary TB most likely appears as infiltrate with hilar adenopathy  Clinical presentation of TB similar in HIV- infected and HIV-uninfected children  Extrapulmonary: marrow, lymph node, bone, pleura, pericardium, peritoneal

8. July 2009 8 www.aidsetc.org Mycobacterium tuberculosis: Diagnosis  Difficult to diagnose; maintain a degree of suspicion  M tuberculosis detected in up to 50% of gastric aspirate in HIV-uninfected children (obtain 3 consecutive morning gastric aspirates)  Usually requires linking TB in child to contact along with positive radiograph, positive skin test (TST), or physical examination

9. July 2009 9 www.aidsetc.org Mycobacterium tuberculosis: Diagnosis (2)  Cornerstone for latent TB is the TST  TST not of value if BCG immunization has been administered  Annual TB testing recommended for HIV- infected children  HIV-infected children may have a negative TST  Sensitivity to TST may be reduced if other viral infection, such as measles, is present

10. July 2009 10 www.aidsetc.org Mycobacterium tuberculosis: Diagnosis (3)  Assays for interferon gamma release following stimulation of lymphocytes have been approved by the FDA for diagnosis of TB (eg, QuantiFERON-TB)  Tests for sputum using nucleic acid amplification approved but not fully evaluated in children  Patients with a positive test for latent TB infection (LTBI) should have any chest radiograph and clinical evaluation to rule on active disease

11. July 2009 11 www.aidsetc.org Mycobacterium tuberculosis: Diagnosis (4) MDR TB should be suspected in a child with TB disease if the child has:  Close contact with the patient with MDR TB  Contact with a TB patient who died while on treatment when there is reason to suspect MDR TB  Bacteriologically proven TB that has not responded to first-line drugs  Exposure to source cases that remain smear or culture positive 2 months after treatment  History of living in a region with a high prevalence of MDR TB

12. July 2009 12 www.aidsetc.org Mycobacterium tuberculosis: Prevention  Children who are homeless, live in institutional settings, or have close family contacts in communities with high rates of coinfection with TB and HIV are particularly susceptible  BCG immunization is not routinely administered in the United States and should NOT be administered to HIV-infected children because of risk of BCG dissemination  Treat HIV-infected children for LTBI if they have a positive TST result

13. July 2009 13 www.aidsetc.org Mycobacterium tuberculosis: Prevention (2)  HIV-infected children should be treated if they are exposed to a person who has contagious TB  Duration of preventive treatment for children should be 9 months with isoniazid 10-15 mg/kg/day (A II) or 20-30 mg/kg twice weekly (B II)  If isoniazid resistance is suspected, use rifampin for 4-6 months

14. July 2009 14 www.aidsetc.org Mycobacterium tuberculosis: Treatment  Treatment principles similar in HIV-infected and HIV-uninfected children  Initiate treatment as soon as possible in children with suspected TB  If already on ART, review drug interactions  Use of DOT increases adherence, decreases resistance, treatment failure, and relapse

15. July 2009 15 www.aidsetc.org Mycobacterium tuberculosis: Treatment (2) Initial treatment (induction phase)  4 drugs: isoniazid, rifampin, pyrazinamide, plus either ethambutol or streptomycin (A I)  If the organism is found to be susceptible to isoniazid, rifampin, and pyrazinamide during the 2-month intensive phase, ethambutol (or streptomycin) can be discontinued  Use ethionamide as alternative to ethambutol for CNS disease (A III)

16. July 2009 16 www.aidsetc.org Mycobacterium tuberculosis: Treatment (3)  If clinical response occurs and organism is susceptible to isoniazid and rifampin after 2 months, continue treatment with isoniazid and rifampin 2-3 times weekly or daily during the continuation phase  Children with severe immunosuppression should receive only daily or 3-times-weekly treatment during the continuation phase  Ethionamide can be used as alternative to ethambutol for TB meningitis  Minimum treatment is 6-9 months for children with active pulmonary TB and 12 months for extrapulmonary disease (A III)

17. July 2009 17 www.aidsetc.org Mycobacterium tuberculosis: Treatment (4) Isoniazid  Dosage: 10-15 mg/kg orally once daily (maximum 300 mg daily)  Hepatic toxicity increases with rifampin  Peripheral neuritis, mild CNS toxicity, gastric upset

18. July 2009 18 www.aidsetc.org Mycobacterium tuberculosis: Treatment (5) Rifampin  Dosage: 10-20 mg/kg orally once daily (maximum 600 mg daily)  Side effects include rash; hepatitis; jaundice; GI upset; orange coloring of urine, tears, sweat  Rifampin can accelerate clearance of PIs (except RTV) and NNRTIs

19. July 2009 19 www.aidsetc.org Mycobacterium tuberculosis : Treatment (6) Rifabutin (B III)  Dosage: 10-20 mg/kg orally once daily  Limited data in children  Peripheral leukopenia, elevated liver enzymes, pseudojaundice, GI upset  Increases hepatic metabolism of certain PIs: reduce rifabutin dosage by 50% when given with RTV, IDV, NFV, APV  Increase dosage of rifabutin by 50-100% when given with EFV

20. July 2009 20 www.aidsetc.org Mycobacterium tuberculosis: Treatment (7) Pyrazinamide  Dosage: 20-40 mg/kg orally once daily (maximum 2 g daily)  Hepatic toxicity, rash, arthralgia, GI upset Ethambutol  Dosage: 15-25 mg/kg orally daily (maximum 2.5 g daily)  Toxicity includes optic neuritis, rash, nausea

21. July 2009 21 www.aidsetc.org Mycobacterium tuberculosis: Treatment (8) Secondary drugs  Ethionamide: 15-20 mg/kg orally divided into 2 or 3 doses daily (maximum dosage 1 g daily)  Streptomycin: 20-40 mg/kg daily IM (maximum dosage 1 g daily)  Alternatives: kanamycin, amikacin, capreomycin, quinolones, cycloserine, paraaminosalicylic acid  Steroids may be indicated for TB meningitis

22. July 2009 22 www.aidsetc.org Mycobacterium tuberculosis: Treatment (9)  Treatment of TB in setting of ART may be complicated by unfavorable pharmacokinetic interactions and overlapping toxicities  Use of rifampin precludes treatment with protease inhibitors but may allow treatment with NNRTIs  Starting treatment with NNRTIs is preferred because of fewer interactions with rifampin-based TB therapy (B II)  Efavirenz is the preferred NNRTI for children >3 years of age whereas nevirapine is preferred for children <3 years of age

23. July 2009 23 www.aidsetc.org Mycobacterium tuberculosis: Treatment (10)  Children already receiving ART should receive immediate treatment for TB accompanied by a review of overlapping toxicities and drug-drug interactions  Drug-resistant TB should be treated with a minimum of 3 drugs, including 2 or more bactericidal isolate-susceptible drugs  Regimens may include 3-6 drugs  Adjunct treatment with corticosteroids may be indicated for children with TB meningitis

24. July 2009 24 www.aidsetc.org Mycobacterium tuberculosis: Monitoring and Adverse Effects  Monthly monitoring of clinical and bacteriological responses to treatment  Side effects of drugs include nausea, vomiting, hepatotoxicity, nephrotoxicity, and optic neuritis with ethambutol  IRIS associated with new onset of systemic symptoms in HIV-infected individuals receiving ART  Data on occurrence of IRIS in children are incomplete  Treatment with corticosteroids has been used in severe cases

25. July 2009 25 www.aidsetc.org Mycobacterium avium Complex Disease: Epidemiology  Multiple related species of non-TB mycobacteria: M avium, M intracellulare, M paratuberculosis  Second most common OI in children after PCP but decreases in incidence with ART  Associated with soil exposure and racial susceptibility  Acquired by means of inhalation, ingestion, or inoculation

26. July 2009 26 www.aidsetc.org Mycobacterium avium Complex Disease: Epidemiology (2)  72% of children with isolated pulmonary MAC develop disseminated MAC by 8 months  May appear as isolated lymphadenitis  Frequency increases with age and declining CD4 T-cell count

27. July 2009 27 www.aidsetc.org Mycobacterium avium Complex Disease: Prevention  Most effective means of prevention is to preserve immune function with ART  Offer prophylaxis for MAC as follows: (A II)  CD4 T-cell risk factor for occurrence:  6 years  Use either clarithromycin or azithromycin (A II)  Studies suggest that prophylaxis may be discontinued when CD4 percentages reach 20% to 25% while on stable ART

28. July 2009 28 www.aidsetc.org Mycobacterium avium Complex Disease: Clinical Manifestations  Recurrent fever, weight loss, failure to thrive, neutropenia, night sweats, chronic diarrhea, malabsorption, abdominal pain  Lymphadenopathy, hepatomegaly, splenomegaly  Respiratory symptoms uncommon among children  Laboratory abnormalities include anemia, leukopenia, and thrombocytopenia

29. July 2009 29 www.aidsetc.org Mycobacterium avium Complex Disease: Diagnosis  Isolation of organism from biopsy, blood, bone marrow, lymph node, or other tissue  Histology demonstrating macrophage containing acid-fast bacilli strongly indicates MAC  Culture is essential for differentiating from TB  Isolation from stool or respiratory does not necessarily indicate invasive disease

30. July 2009 30 www.aidsetc.org Mycobacterium avium Complex Disease: Treatment  Preserve immune function through optimal treatment of HIV infection  Initiate treatment with 2 or more drugs (eg, clarithromycin or azithromycin plus ethambutol) (A I)  Consider rifabutin as third drug in severely ill patients (C I)  Caution in using rifabutin as it may increase toxicity of other ARVs and increase clearance of PIs and NNRTIs

31. July 2009 31 www.aidsetc.org Mycobacterium avium Complex Disease: Treatment (2)  Note cautions in use of these drugs with ARVs  If rifabutin cannot be used or if drug failure occurs, consider ciprofloxacin, amikacin, streptomycin, and a quinolone  Lifelong suppressive therapy required after initial therapy  IRIS may occur as indicated by new onset of symptoms  Toxicities of drugs include nausea, vomiting, liver toxicity, hypersensitivity reactions and, with ethambutol, optic neuritis

32. July 2009 32 www.aidsetc.org Mycobacterium avium Complex Disease: Treatment (3)  Clarithromycin: 7.5-15 mg/kg orally twice daily (maximum 500 mg twice daily) (A I)  Azithromycin: 10-12 mg/kg once daily (maximum 500 mg daily) (A II)  Ethambutol: 15-25 mg/kg single oral dose (maximum 1 g) (A I)

33. July 2009 33 www.aidsetc.org Mycobacterium avium Complex Disease: Treatment (4)  Rifabutin: 10-20 mg/kg orally once daily (maximum 300 mg daily) (A I)  Ciprofloxacin: 20-30 mg/kg IV or orally once daily (maximum 1.5 g)  Amikacin: 15-30 mg/kg/day IV divided every 12-24 hours (maximum 1.5 g) (C III)

34. July 2009 34 www.aidsetc.org  This presentation was prepared by Arthur Ammann, MD, Clinical Professor of Pediatrics University of California and President of Global Strategies for HIV Prevention for the AETC National Resource Center, in July 2009  See the AETC NRC website for the most current version of this presentation: http://www.aidsetc.org About This Slide Set