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NORTHWEST AIDS EDUCATION AND TRAINING CENTER MAC & HIV in 2015 Tom Hawn, MD Division of Allergy & Infectious Disease January 8, 2015 Presentation prepared by: Presenter Last Updated: January 8, 2015 Outline & Some Questions 1. Susceptibility: • Why do HIV patients get MAC? 2. Clinical Presentation 3. Treatment • When do you check sensitivities? • How many drugs? • IRIS Risk & Management I. Why: Relevance & Susceptibility NTM Microbiology • • • • NTMs ~140 species Environmental Source Daily Exposure Non-Tuberculous Mycobacteria (NTM) Phylogeny Microbiology: The Confusing Convention MAC, MAI: What’s In a Name? Species MAC Mycobacterium avium Complex M. avium M. intracellulare Reservoir Environment & birds Environment Plus More Confusion Species M. avium subsp avium Reservoir Disease environment birds (Avian TB) M. avium subsp hominissuis environ. humans M. avium subsp paratuberculosis environ. ruminants (Johne’s Dz) ?humans M. intracellulare environ. humans Turenne, Wallace, Behr Clin Micro Reviews 2007 MAC Epidemiology 1. Exposure & Infection is Common 2. May alter susceptibility to TB Disease 3. May alter immune response to BCG vaccination M. intracellulare (PPD-B) Sensitization Rates US 1999-2000: 16.6% (Khan & Marras AJRCCM 2007) Palmer & Edwards JAMA 1966; Black, Fine, Dockrell Lancet 2002; Weir et al Clin Exp Immunol 2006 NTM Epidemiology WA State MAC (N=587) Emily Ford, MD Carolyn Wallis, Clinical Technologist Lead, HMC Laboratory Medicine, Microbiology Study Design: • Retrospective chart review, 1998-2011 • N = 972 UW/HMC subjects with Cx + clinical data • N= 587 MAC (74 from blood) (most common NTM) Risk Factor (N) % Positive Male (564) 65.0% (367) Smoking (40) 52.5% (21) EtOH abuse (40) 30% (12) Homelessness (40) 15% (6) IVDU (39) 15% (6) HIV (233) 36.5% (85) Jail (34) 20.6% (7) Immunosupp. (40) 17.5% (7) Malignancy (40) 25% (10) Diabetes (40) 20% (8) Transplant (40) 10% (4) COPD (40) 10% (4) Positive PPD (21) 38.1% (8) Any data about exposure risk for HIV patients? MAC Risk Factors: Is it the Host or Environment? Design: Matched case-control, 2007+ Determine whether aerosol generating activity, water supply, or host factors are associated with MAC lung disease Cases: ATS case criteria, passive recruitment, N=70 Excluded HIV and Cystic Fibrosis Patients Controls: random digit phone dialing, matched by age-group, sex From A Specific Environmental Source? No Immunology, IFNg, & Mycobacteria Children & Mendelian Adults & Acquired Mostly BCG, NTMs. Salmonella 1. HIV: MAC, MTb, Crypto, Histo, Salmonella, Penicillium et al Mf orMf DC or DC Mutations IKKg (NEMO) IL-12p40 IL-12R IFNgR1 IFNgR2 STAT1 IKKg (NEMO) IL-12 T cell IL-12R IFNgR STAT1 MICROBIAL KILLING Lesson: MAC = IFNg + additional T-cell Defect IFNg 2. Anti-IFNg Ab NTMs (MAC + many others), MTb, VZV, Crypto, Histo, Salmonella, Penicillium Casanova & Abel Annu Rev Imm (2002); Browne NEJM 2012 II. MAC Clinical Presentation II. MAC Clinical Presentation 3 Classic presentations: 1. Male, smoker, apical fibrocavitary disease 2. Female, non-smoker, nodular, bronchiectasis, often RML & lingula 3. HIV Disseminated Disease Annual Disease Incidence: 4.7 cases/100k HIV & Disseminated MAC Symptom Percentage Fever Night sweats Anorexia Weight loss Hepatomegaly Diarrhea Splenomegaly Abdominal Pain 87 78 74 38 42 47 32 35 Anemia Elevated Alk Phos 85 53 Havlik JID 1992, Benson CID 1994 MAC Diagnosis 1. Disseminated Dz: • One Positive Blood Culture or • Positive culture from sterile site 2. Pulmonary MAC CT: bilateral nodular densities and bronchiectasis. NTM ATS Guidelines: Griffith et al Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases. AJRCCM 175: 367-416 (2007); Kasperbauer & Daley Sem Resp Crit Care Med 2008 III. Treatment HIV Guidelines: MAC Prevention Indication CD4<50 after ruling out active MAC dz Preferred Azithromycin 1200 mg po q wk (AI) Clarithromycin 500 mg po bid (AI) or Azithromycin 600 mg po 2x/wk (BIII) Alternative Rifabutin 300 mg po qday (BI) HIV Guidelines: MAC Rx Preferred: At least 2 drugs Clarithro + Ethambutol (AI) or Azithro (AII) + Ethambutol (AI) (to avoid drug interactions) Alternative: Consider 3rd or 4th drug with advanced HIV, high CFU load, or absence of ART Options include: Rifabutin (CI), Aminoglycoside (CIII), or FQ (CIII) HIV MAC Rx Response ~40% overall CAVEAT: Some studies in pre-HAART & mostly in early ART era Meta-analysis of 28 trials and 2422 patients Xu Eur J Clin Micro Resp Dis 2013 NTM Abx Sensitivities: Should you check? YES Growth Species Rapid Chelonae Abscessus Fortuitum Susceptibility Testing Slow MAC Kansasii Marinum Clarithromycin/Azithromycin Rifampin (multiple if Rif Rest) Not routinely Griffith NTM ATS Guidelines AJRCCM 2007 Yes Multiple Abx Pulmonary MAC Rx 1. Macrolides matter 2. √ macrolide sensitivity: predicts success Macrolide: YES NO Meta-analysis of 28 trials and 2422 patients Xu Eur J Clin Micro Resp Dis 2013 Rifamycin Drug Interactions • Rifampin: most potent known inducer of Phase I. Also induces Phase II. Cyto P450 Induction Rifampin:1A2, 2C9, 2C19, 3A4, 2D6 Rifabutin: 3A4 Rifapentine: 2C9, 3A4 Potency 1 0.4 0.85 Rifabutin substitution can be useful to minimize needs for drug dose changes with: HIV protease inhibitors, methadone, cyclosporine (with drug level monitoring) BCP: add barrier method for any rifamycin Rifamycin Drug Substitutions Some common desirable substitutions when using any rifamycin: Avoid Simvastatin, Fluvastatin, Atorvastatin Clarithromycin Keto, Itra, Voriconazole Losartan Metoprolol Prefer Rosuvastatin Azithromycin Fluconazole (with dose increase) Valsartan Atenolol HIV Guidelines: Discontinuing MAC Rx Continue MAC Rx until: 1. At least 12m Rx 2. Clinical cure 3. CD4>100 x 6m on ART (A-II Recommendation) HIV Guidelines: MAC & IRIS Initiate ART Rx as soon as possible after 2 wks of MAC Rx If IRIS develops, consider: A. NSAIDS for moderate to severe Sxs (CII) B. If sxs persist, prednisone 20-40 mg po qday x 4-8 wks MAC & IRIS Median Time to IRIS 2.6m (range 10d to 4.7 y) Mean CD4=24 3 sites: LN, GI, Liver 80% Response Rate • Retrospective Chart Review 1996-2004 • N=20 cases of MAC IRIS • Definition: Cx or PCR confirmed IRIS after starting ART with 6m of follow-up Riddell et al J Transl Med 2007 Summary Points 1. Risk: IFNg is important, but additional T-cell defects matter. 2. Diagnosis: 1 positive Bld Cx for disseminated. Distinguish colonization from disease for pulmonary MAC 3. Rx: Multidrug & lengthy. 2 drugs generally OK for HIV disseminated MAC 4. Macrolides are essential—check sensis 5. Be attentive to rifamycin drug interactions in Rx of all mycobacteria 6. IRIS: minimal data to guide Rx, start ART soon after 2 wks of MAC Rx Review References • CDC/HIVMA/IDSA OI Guidelines May 2013: (http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf). • Karakousis, Moore, Chaisson. MAC Treatment & HAART. Lancet ID 4: 557 (2004) • NTM ATS Guidelines: Griffith et al Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases. AJRCCM 175: 367-416 (2007) Pulmonary MAC Rx • Length, schedule, & #Abx varies depending on presentation Kasperbauer & Daley Sem Resp Crit Care Med 2008 Pulmonary NTM Epidemiology NTM N Global NTM-NET USA Good Scotland Russell Oregon Cassidy WA Ford 18010 11391 933 407 787 2008, P 1980, all 1997, P 2005,P 1998-2011 MAC 9421 6979 418 344 475 M. xenopi 1605 85 42 3 9 M. fortuitum 1322 1584 13 3 30 M. kansasii 720 1133 36 1 24 M. abscessus 664 128 7 38 Year, site M. scrofulaceum 763 M. chelonae 543 M. malmoense M. simiae 1 24 1 10 202 0 17 5 * M. gordonae excluded. Hoefslott 2013, Good 1980, Russell 2013, Cassidy 2009, Ford unpublished