N ORTHWEST AIDS E DUCATION AND T RAINING C ENTER MAC & HIV in 2015 Tom Hawn, MD Division of Allergy...
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Transcript of N ORTHWEST AIDS E DUCATION AND T RAINING C ENTER MAC & HIV in 2015 Tom Hawn, MD Division of Allergy...
NORTHWEST AIDS EDUCATION AND TRAINING CENTER
MAC & HIV in 2015
Tom Hawn, MD Division of Allergy & Infectious DiseaseJanuary 8, 2015
Presentation prepared by: PresenterLast 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 ReservoirMACMycobacterium avium Complex
M. avium Environment & birdsM. intracellulare Environment
Plus More Confusion
Turenne, Wallace, Behr Clin Micro Reviews 2007
Species Reservoir Disease
M. avium subsp avium environment birds
(Avian TB)
M. avium subsp hominissuis environ. humans
M. avium subsp paratuberculosis environ. ruminants
(Johne’s Dz)
?humans
M. intracellulare environ. humans
MAC Epidemiology
1. Exposure & Infection is Common
2. May alter susceptibility to TB Disease
3. May alter immune response to BCG vaccination
Palmer & Edwards JAMA 1966; Black, Fine, Dockrell Lancet 2002; Weir et al Clin Exp Immunol 2006
M. intracellulare (PPD-B) Sensitization Rates
US 1999-2000: 16.6%(Khan & Marras AJRCCM 2007)
NTM Epidemiology WA State
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)
Emily Ford, MDCarolyn Wallis, Clinical Technologist Lead, HMC Laboratory Medicine, Microbiology
MAC (N=587)
Any data about exposure risk for HIV patients?
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)
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 PatientsControls: random digit phone dialing, matched by age-group, sex
From A Specific Environmental Source? No
Immunology, IFNg, & Mycobacteria
Casanova & Abel Annu Rev Imm (2002); Browne NEJM 2012
Adults & Acquired 1. HIV: MAC, MTb, Crypto, Histo, Salmonella, Penicillium et al
Lesson: MAC = IFNg + additional T-cell Defect
T cell
M f or DC
IL-12R
IL-12
IFNg2. Anti-IFNg AbNTMs (MAC + many others),
MTb, VZV, Crypto, Histo, Salmonella, Penicillium
IFNgR
MutationsIKK g( )NEMOIL-12p40IL-12RIFNgR1IFNgR2STAT1
MICROBIAL KILLING
Children & Mendelian Mostly BCG, NTMs.Salmonella
STAT1
M f or DC
IKK g (NEMO)
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 PercentageFever 87Night sweats 78Anorexia 74Weight loss 38Hepatomegaly 42Diarrhea 47Splenomegaly 32Abdominal Pain 35
Anemia 85Elevated Alk Phos 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% overallCAVEAT: Some studies in pre-HAART & mostly in early ART era
Xu Eur J Clin Micro Resp Dis 2013
Meta-analysis of 28 trials and 2422 patients
NTM Abx Sensitivities: Should you check?
Griffith NTM ATS Guidelines AJRCCM 2007
Growth Species Susceptibility TestingRapid Chelonae
Abscessus YesFortuitum Multiple Abx
Slow MAC Clarithromycin/AzithromycinKansasii Rifampin (multiple if Rif Rest)Marinum Not routinely
YES
Pulmonary MAC Rx
1. Macrolides matter
2. √ macrolide sensitivity: predicts success
Xu Eur J Clin Micro Resp Dis 2013
Macrolide:YES
NO
Meta-analysis of 28 trials and 2422 patients
Rifamycin Drug Interactions
• Rifampin: most potent known inducer of Phase I. Also induces Phase II.
Cyto P450 Induction PotencyRifampin:1A2, 2C9, 2C19, 3A4, 2D6 1Rifabutin: 3A4 0.4Rifapentine: 2C9, 3A4 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 PreferSimvastatin, Fluvastatin, Atorvastatin RosuvastatinClarithromycin AzithromycinKeto, Itra, Voriconazole Fluconazole
(with dose increase)
Losartan ValsartanMetoprolol Atenolol
HIV Guidelines: Discontinuing MAC Rx
Continue MAC Rx until:
1. At least 12m Rx2. Clinical cure3. 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
• 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
Median Time to IRIS2.6m (range 10d to 4.7 y)Mean CD4=24
3 sites: LN, GI, Liver
80% Response Rate
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
* M. gordonae excluded. Hoefslott 2013, Good 1980, Russell 2013, Cassidy 2009, Ford unpublished
Pulmonary NTM Epidemiology
NTM GlobalNTM-NET
USAGood
ScotlandRussell
OregonCassidy
WAFord
N 18010 11391 933 407 787
Year, site 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
M. scrofulaceum 763 1
M. chelonae 543 24 1 10
M. malmoense 202 0
M. simiae 17 5