N ORTHWEST AIDS E DUCATION AND T RAINING C ENTER MAC & HIV in 2015 Tom Hawn, MD Division of Allergy & Infectious Disease January 8, 2015 Presentation prepared.

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