Short-Course Therapy for MDR-TB 1

[Are we ready to try the]Short(er) Course Regimen 

for MDR TB?Pennan Barry, MD MPH

Chief, Surveillance and EpidemiologyMD Lead, California MDR TB Service

California TB Control Branch

(Many slides courtesy Charles Daley)March 8, 2017

Curry CTCA Course

Short(er) Course Regimen for MDR-TB

Outline

• Current treatment approach

• Short course regimen

• Implications for high‐resource, low incidence areas like California

• Barriers to implementation

Group A Group B Group C Group D

Fluoroquinolone Second‐line injectable

Other Core Second‐line

Add‐on agents

Levofloxacin         

Moxifloxacin

Gatifloxacin

Amikacin

Capreomycin

Kanamycin

(Streptomycin)

Ethionamide/Prothionamide

Cycloserine/

Terizidone

Clofazimine

Linezolid 

D1: Pyrazinamide

Ethambutol

High‐dose INH

D2: Bedaquiline

Delamanid

D3: P‐aminosalicylic acid

Imipenem/meropenem

Amoxacillin/Clavulanate

(Thioacetazone)

New Grouping of MDR‐TB Drugs

Short-Course Therapy for MDR-TB 2

Building a Treatment Regimenwith 2016 Update

Step 1 Group A (one)Levofloxacin MoxifloxacinGatifloxaxin

Step 2

Step 3 Group C (two)Ethionamide/Prothionamide ClofazimineCycloserine/Terizidone Linezolid

Step 4 Group D1 Pyrazinamide (include) Ethambutol* High-dose INH*Group D2Bedaquiline DelamanidGroup D3Imipemen/Meropenem Amoxacillin/ClavulanateP-aminosalicylic acid

≥5 likely effective including 4 core drugs, PZA andconsider*

Group B (one)KanamycinAmikacin Capreomycin

Treatment of MDR-TBDuration of Therapy

• An intensive phase of at least 8 months’duration is recommended

(conditional recommendation, very low quality of evidence)

• A total treatment duration of at least 20months is recommended in patientswithout any previous MDR-TB treatment

(conditional recommendation, very low quality of evidence)

WHO 2011 Update

Treatment Outcomes in Patients with MDR‐TB, 2007‐2012 Cohorts

50%

WHO, Global Tuberculosis Report 2015

Short-Course Therapy for MDR-TB 2a

Short Course Standardized Regimen for MDR-TB

Van Deun, et al. Am J Respir Crit Care Med 2010;182:684-692

Completion – 5.3% Death – 5.3%Cure – 82.5% Default – 5.8%Success – 87.8% Failure – 0.5%

Relapse – 0.5%

4(+)KCGEHZP/5 GEZC

Countries Using Short(er) Course MDR‐TB Regimen

Short-Course Therapy for MDR-TB 3

Short Course Standardized Regimen for MDR-TB

Regimen Intensive Continuation Number Cum. % Treatment Success %

1 3KCOEHZP 12 OEHZP 59 13.868.92 3(+)KCOEHZP 12 OEHZP 44 10.3

3 3(4)KCOEZP 12 OEZP 35 8.2 57.1

4 3(+)KCOEHZP 12 OHEZ 45 10.5 66.7

5 3(+)KCOEHZP 12 OHEZC 38 8.9 84.2

6 4(+)KCGEHZP 5 GEZC 206 48.2 87.8

427 100.00

C = clofazimine, E = ethambutol, G = gatifloxacin, H = isoniazid, K = kanamycin, O = ofloxacin, P = prothionamide, Z = pyrazinamide

3(4) = minimum of 3 mos, prolonged to 4 months if no conversion by end of 3 mos3(+) = minimum of 3 mos, prolonged until conversion achieved4(+) = minimum of 4 mos, prolonged until conversion achieved

Van Deun, et al. Am J Respir Crit Care Med 2010;182:684-692

Short Course Standardized Regimen for MDR-TB

Van Deun, et al. Am J Respir Crit Care Med 2010;182:684-692

Completion – 5.3% Death – 5.3%Cure – 82.5% Default – 5.8%Success – 87.8% Failure – 0.5%

Relapse – 0.5%

4(+)KCGEHZP/5 GEZC

Countries Using Short(er) Course MDR‐TB Regimen

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Short-Course Therapy for MDR-TB 4

WHO Policy RecommendationShorter Course MDR-TB Regimen

Recommendation:

In patients with RR or MDR-TB • who have not been treated with second-

line drugs and• in whom resistance to FQNs and SLI

agents has been excluded or is considered to be highly unlikely

a shorter MDR-TB regimen of 9-12 mos may be used instead of a conventional regimen

WHO 2016 Update

(conditional recommendation, very low certainty in the evidence)

Short(er) Course Regimen for MDR-TB

Isoniazid*

Moxifloxacin*

Pyrazinamide

Ethambutol

0 1 2 3 4 5 6 7 8 9+

months

Clofazimine

Prothionamide

Kanamycin

Initial Phase (7 drugs) Continuation Phase (4 drugs)

*High dose

WHO Guideline Drug Doses

http://www.who.int/tb/areas‐of‐work/drug‐resistant‐tb/treatment/FAQshorter_MDR_regimen.pdf December 2016

Choosing the M

DR‐TB Regimen

Short-Course Therapy for MDR-TB 4a

Short-Course Therapy for MDR-TB 5

Choosing the MDR‐TB Regimen

Treatment Success*Shorter vs. Conventional Regimens

Resistance pattern Shorter MDR‐TB Regimen (N=1116)

Conventional MDR‐TB Regimen 

(N = 5850)

All cases 90.3% 78.3%

PZA susceptible;FQN susceptible

96.8% 83.5%

PZA resistant;FQN susceptible

88.8% 81.4%

PZA susceptible;FQN resistant

80.0% 64.4%

PZA resistant;FQN resistant

67.9% 59.1%

*Treatment success – cure or completedWHO 2016 Update

Decreasing success

Studies Analyzed for WHO Guidelinehttp://apps.who.int/iris/bitstream/10665/250125/5/9789241549639‐webannexes‐eng.pdf?ua=1

BANGLADESH 2005–2011

NIGER 2008–2010

CAMEROON 2008–2011

UZBEKISTAN 2013–2015

MULTIPLE 2013–2015

SWAZILAND 2014–2015

Status  Published  Published  Published  Ongoing  Ongoing  Ongoing

Data on Relapse(2 yrs p Rx)?

Yes Yes No No No No

Eligible 640 124 323 NR 1169 114

MDR or RIF‐R confirmed

527† 97† 237† 117* 1169** 76*

Excluded 34 (6.4%) 32 (33.0%) 87 (36.7%) 52 (44.4%)Ω761 

(65.1%)***52 (68.4%) 

Ω

Included 493 (93.5%) 65 (67.0%) 150 (63.3%) 65 (55.6%) 408 (34.9%) 24 (31.5%)

*** 409/761 never initiated short regimen: 65 with prior exposure to second‐line drugs; 1 with XDR‐TB; 112 lost prior to initiation; 34 died prior to initiation; 197 other.

ΩMajority of exclusions were accounted for by participants in whom short MDR‐TB treatment was ongoing, or had ended recently: Uzbekistan, 39/52; Swaziland, 47/52.

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Short-Course Therapy for MDR-TB 6

Extent of Disease

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%Smear positive

http://apps.who.int/iris/bitstream/10665/250125/5/9789241549639‐webannexes‐eng.pdf?ua=1

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%Cavity on CXR

PZA and EMB Resistance

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%EMB ‐R

http://apps.who.int/iris/bitstream/10665/250125/5/9789241549639‐webannexes‐eng.pdf?ua=1

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%PZA‐R

Eligibility For Short‐course Regimen for MDR‐TB in Europe

Cohort Drug Resistance in MDR‐TB (%)Eligible for Short‐CourseRegimen

N SLID FQ Pto/Eto

E Z N %

Austria 80 41 25 48 64 63 8 10

France 114 30 32 71 65 59 7 6

Germany 70 23 27 57 80 73 6 9

Portugal 200 51 48 83 52 75 9 5

TBnet* 148 28 21 47 54 62 18 12

Total 612 37 33 64 60 67 48 8

*16 countries in EuropeLange C, et al. AJRCCM 2016;194:1029

Short-Course Therapy for MDR-TB 6a

Projected Incidence of MDR‐TB with Different Regimens

Assumptions: Short-course regimen would double treatment access and achieve long-term efficacy seen in cohort studies

-23%

Kendall EA , et al. Lancet 2016, epub

Projected Incidence of MDR‐TB with Different Regimens

Assumptions: 30% of MDR-TB case ineligible

-2%

Kendall EA , et al. Lancet 2016, epub

Short-Course Therapy for MDR-TB 7

Projected Incidence of MDR‐TB with Different Regimens

Assumptions: Short-course regimen would double treatment access and achieve long-term efficacy seen in cohort studies

-23%

Kendall EA , et al. Lancet 2016, epub

Projected Incidence of MDR‐TB with Different Regimens

Assumptions: 30% of MDR-TB case ineligible

-2%

Kendall EA , et al. Lancet 2016, epub

Barriers to Implementing

• Clofazimine availability

• Full DST info  few qualify by strict criteria

• How to substitute for adverse events orresistance

• Disbelief in regimen – “Why does it work?”

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Short-Course Therapy for MDR-TB 8

Global Barriers to Implementation of Shorter Course MDR‐TB Regimen

• Laboratory

– Availability of SL‐LPA

– Availability of phenotypic DST

• Drugs

– Availability of clofazimine

– Lack of pediatric formulations of clofazimine

– Avoiding stock‐outs of drugs

Acknowledgments

• Chuck Daley

• Faiz Khan

• Neha Shah

• California MDR Service