short-course therapy for mdr-tb 1...short-course therapy for mdr-tb 3 short course standardized...
Post on 16-Oct-2020
6 Views
Preview:
TRANSCRIPT
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
(Larger image on previous page)
(Larger image on previous page)
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.
(Larger image on previous page)
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?”
(Larger image on previous page)
(Larger image on previous page)
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
top related