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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