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Impact of Number of Drugs, Treatment Duration and PZA on MDR TB Treatment Outcomes
Carole D. Mitnick, ScD Harvard Medical School & Partners In Health NAR/NCTA 27 Feb 2016
1998
2016
MDR among 1.4% of new and 13% of previously treated in 35 countries
Summary o Overview of needs in MDR treatment o Questions around treatment decisions
n # of drugs (combinations) n PZA n duration
o Doing better with what we have o Prospects for revolutionizing MDR-TB
treatment
Prevalence of MDR-TB among new TB cases
Prevalence of MDR-TB among previously treated TB cases
480,000 MDR among new TB Cases
123,000 (26%) MDR cases reported
111,000 (23%) treated 11.5% expected
success
Outcomes on existing MDR-TB treatment
1WHO Global Report, 2014; 2Orenstein, Lancet, 2009*; 3Johnston, PLoS, 2009*; 4Diacon, NEJM, 2014; 5Skriponoca, ERJ, 2013; 6Ahuja, PLoS, 2012*; 7Bonnet et al, IJTLD, 2016
50%
62% 62%
32%
55% 54% 56%
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80%
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Frequency of adverse events (or AE indicating drug removal) on existing MDR-TB treatment
0
10
20
30
40
50
60
70
80
90
100
FDA AIAC briefing, bedaquiline, Nov 2012
Gler et al, 2012, supplementary
material
Nathanson, IJTLD, 2004
Pill burden
Photo: Daily MDR-TB regimen in Mozambique. Why we're investing w/ @PIH, IRD & @MSF for better treatment! pic.twitter.com/j7zovDfIQ3 (UNITAID Twitter feed May 7, 2014)
Morning dose Evening dose
Pyrazinamide: 4 tablets
Kanamycin: 1 g IM
Levofloxacin: 2 tablets
Ethionamide: 1 tablet
Cycloserine: 1 capsule
PAS: 1 sachet
AZT/3TC combination: 1
tablet Cotrimoxazole: 1
tablet
Ethionamide: 2 tablets
Cycloserine: 2 capsules
PAS: 1 sachet Pyridoxine: 4
tablets
AZT/3TC combination: 1
tablet EFV (600 mg): 1
tablet
TypicalDailyPillBurdenforMDR-TB/HIVCo-infectedPa<ent>60kg
Cost of current MDR-TB treatment
Regimen description
Drugs
Price Range for Regimens Using Quality-Assured
ProductsStandard Regimen
for MDR-TB in Settings with No SLD Resistance
pyrazinamide, kanamycin, levofloxacin, ethionamide, cycloserine
USD $1,344 - $2,222
Regimen for Patients with SLD
Resistance
pyrazinamide, capreomycin, moxifloxacin, ethionamide,
cycloserine, PAS
USD $5,267 - $7,339
Regimen for XDR-TB or Failures of
MDR-TB Treatment
capreomycin, moxifloxacin, cycloserine,
clofazimine, linezolid, meropenem
USD $14,244 - $15,356
Questions
#, composition, and duration
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Doing Better With What we Have: Number of Drugs (& Composition)
o How many drugs are required to treat MDR-TB successfully? n Which drugs n How can toxicity be minimized n Other considerations, e.g.,
costs & logistics
Current WHO treatment guidelines (2011)
o Total duration of 20 months
o Intensive phase of 8 months
o Use 4 drugs (likely susceptible) + PZA during the intensive phase
o Use PZA, FQ, inject, thiomide, CS or PAS
Ahuja et al, PLoS Med, 2012; WHO, 2011; Falzon et al., ERJ, 2011
# of Likely Effective Drugs in Intensive Phase (IPD, N>=5666)
# of LE drugs
aOR (95% CI) failure/relapse
aOR (95% CI) failure/relapse/death
3 1.1 (0.5,2.4) 1.7(1.2,2.5) 4 2.0 (1.1,3.6) 2.7(1.9,3.9) 5 2.0 (1.1,3.6) 2.8(1.7,4.6) 6+ 2.4 (1.0,5.4) 2.1(1.4,3.1)
Ahuja et al, PLoS Med, 2012
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Aggressive Regimen in Peru & Tomsk o Regimen with >=5 likely effective drugs
(Groups 1-IV), including FQ & injectable Applied in: o Mitnick CD, et al. PLoS ONE. 2013:8(3). o Franke MF, et al. Clin Infect Dis. 2013:56(6). o Tierney D, et al. PLoS ONE. 2014:9(9). o Velasquez G, et al., Clin Infect Dis. 2014:59(1).
1Mitnick et al, PLoS One 2013; 2Franke et al, CID, 2012; 3Tierney et al, PLoS One, 2014
Methods1,2,3 o Study population: patients in metro Lima who
received their 1st ITR, 1997-2002 o Classification varied by month: >=75% of
aggressive days/month=aggressive month o Time-varying Cox proportional hazards models o Endpoints: death1, recurrence2, and conversion3 o Adjusted for: age, sex, prior treatment, severity,
comorbidities, resistance
Baseline characteristics1
Results: Outcomes* among 669 patients included in mortality analysis
Outcome N (%)
Cured/completed 442 (66.1)
Treatment Failed 17 (2.5)
Died 129 (20.8)
Defaulted 67 (10.0)
Missing/Transferred out 4 (0.6)
Total 669 (100) *Classified per Laserson et al., IJTLD, 2005
82% received aggressive regimen for ≥1 month; mean duration 21 (IQR:15-26) months
Results1: Aggressive regimen & death (n=669)
1Mitnick et al, PLoS Med 2013
End point: time from initiation of the individualized regimen to death from any cause, while on treatment
Results2: Aggressive regimen & recurrence (n=402)
2Franke et al, CID, 2012
Results3: Rates of culture conversion by semester and treatment type (n=592)
HR0-6:1.36 (95% CI: 1.10,1.69)
Tierney et al., PLoS One, 2014
Number of effective drugs & culture conversion (PETTS, N=1137)
Yuen et al., PLoS Med, 2015
Conclusion # of Drugs o From efficacy standpoint, more is
better n Guided by DST better, untested good too
o Threshold effect?
Why we PZA… o key role in shortening treatment, through
activity against non-replicating persisters
o active against M. tuberculosis in acidic environment
o acts synergistically with RIF (among others)
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Utility of PZA in MDR?
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o 50% of MDR, resistant to PZAL o Only active early in treatment? L o Phenotypic DST challenging:
n Large innoculum can release ammonia, pH increases, PZA activity decreases. S R L
n PZA activity requires an acidic medium…. inhibits Mtb. R S L
o Genotypic tests: n pncA mutation sensitivity?L n No validated test available for routine use L
Treatment Success vs. Failure, Relapse, Death, Individual Patient Data Meta-analysis
Ahuja, et al., PLoS Medicine, 2012
Drug used
N aOR 95%CI
PZA 5096 1.3 1.1,1.6
Question Is the WHO-recommended regimen—four likely effective drugs plus PZA—compromised in individuals in whom PZA is not likely effective?
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5 likely effective drugs, none of which
is PZA*
5 likely effective drugs, one of which is PZA*
4 likely effective drugs, plus
PZA which is not likely effective
Aggressive regimen
WHO-recommended regimen
Primary exposure
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Group C: 5 likely effective drugs, none of which is PZA
Group D: 4 likely
effective drugs, but does not
correspond to category B
Group E: <4 likely effective
drugs
Group A: 5 likely
effective drugs, one of which is PZA
Group B: 4 likely effective
drugs, plus PZA which is
not likely effective
Group F: > 6 likely effective drugs*
Regimen contains a
likely effective injectable?
Group G: Any number of likely effective drugs without
a likely effective injectable
Yes
No
Results: regimen classification
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Group C: 5 likely effective drugs, none of which is PZA*
1,414 person-months (28.3%)
6 deaths
Group D: 4 likely effective drugs, but does
not correspond to category B
951 person-
months (19.1%)19 deaths
Group E: <4 likely effective
drugs
515 person-months (10.3%)
10 deaths
Group A: 5 likely effective
drugs, one of which is PZA*
188 person-
months (3.8%)1 death
Group B: 4 likely effective drugs, plus PZA
which is not likely effective
252 person-
months (5.0%)5 deaths
Group F: > 6 likely
effective drugs*
452 person-months (9.1%)
3 deaths
Regimen contains a likely effective
injectable?
Group G: Any number of likely effective drugs without a likely
effective injectable
1,220 person-months (24.4%)15 deaths
No
Yes
Primary results: Risk of death by regimen exposure
Group Regimen Univariable
Hazard ratio [95% CI]
p-value Multivariable*
Hazard ratio [95% CI]
p-
value
A + C5 LE drugs
Reference Reference
B4 LE drugs, plus PZA not LE 4.40 [1.40, 13.85] 0.01 2.76 [0.92, 8.27] 0.07
D4 LE drugs
4.46 [1.87, 10.60] 0.007 2.87 [1.35, 6.09] 0.006
E<4 LE drugs
4.24 [1.61, 11.14] 0.003 3.36 [ 1.43, 7.85] 0.005
F > 6 LE drugs1.51 [0.39, 5.82] 0.55 1.20 [0.32, 4.45] 0.80
GAny # LE drugs without LE injectable 2.73 [1.11, 6.69] 0.03 1.94 [0.83, 4.53] 0.12
Results: secondary
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Group C: 5 likely effective drugs, none of which is PZA
Group D: 4 likely
effective drugs, but does not
correspond to category B
Group E: <4 likely effective
drugs
Group A: 5 likely
effective drugs, one of which is PZA
Group B: 4 likely effective
drugs, plus PZA which is
not likely effective
Group F: > 6 likely effective drugs*
Group G: Any number of likely effective drugs without
a likely effective injectable
The rates of death for Groups A and C were indistinguishable (aHR: 1.00; CI: 0.12, 8.00).
Statistical analyses: secondary
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Group C: 5 likely effective drugs, none of which is PZA
Group D: 4 likely
effective drugs, but does not
correspond to category B
Group E: <4 likely effective
drugs
Group A: 5 likely
effective drugs, one of which is PZA
Group B: 4 likely effective
drugs, plus PZA which is
not likely effective
Group F: > 6 likely effective drugs*
Group G: Any number of likely effective drugs without
a likely effective injectable
NLE PZA
No PZA
The hazard of death associated with group C regimens that did not include PZA was lower than group C regimens that contained PZA (aHR: 0.10; CI: 0.13, 0.85).
PZA within MV model predicting culture conversion
PZA aHR (95% CI) Yes vs. no, with 1 tested drug
2.00 (1.65,2.41)
Yuen et al., PLoS Med, 2015
# effective drugs
Addition of 1 untested drug aHR (95% CI)
aHR PZA NO aHR PZA YES
3 1.39 (1.09, 1.76) 0.93 (0.77,1.11) 4 1.68 (1.27,2.23) 1.13 (0.91,1.40) 5 2.04(1.42,2.94) 1.37 (1.01,1.85) 6 2.48(1.56,3.95) 1.66(1.10,2.49)
# untested drugs
Addition PZA aHR (95% CI)
0 2.98 (2.08,4.28) 1 2.00 (1.65,2.41) 2 1.34 (0.97,1.84)
Conclusions PZA o Remains important, tested or not o Can’t count on it if untested o Supplement-YES; Replace-yes o Less important if more other drugs
(tested and not) included
Duration o What is the optimal duration of MDR-
TB treatment?
Months of rx aOR (95% CI) 12.6-15.5 1.5 (0.6,3.6) 15.6-18.5 3.6 (1.5,8.7) 18.6-21.5 5.2 (2.0,11.5) 21.6-24.5 4.9 (2.1,11.5) 24.6-27.5 11.7 (4.5,30.2) 27.6-30.5 2.8 (1.0,7.6) 30.6-36 1.2 (0.2,5.8)
Ahuja et al, PLoS Med, 2012
Association of Treatment Duration With Success (IPD, N=4667)
Duration Conclusions o Without any info on likely
effectiveness, longer is better.
Bangladesh-type regimens
Regimen Months Location Success Citation 4+KGfxhdPthHhdCfzEZ 5GfxhdCfzEZ
9+ Bangladesh 85% Aung et al, IJTLD, 2014
4+KGfxPthCfzHhdEZ 8GfxPthCfzEZ
12+ Cameroon 89% Kuaban et al., IJTLD, 2014
4+KGfxhdPthHhdCfzEZ8GfxhdCfzEZ
12+ Niger 85% Piubello et al., IJTLD, 2015
Excluded patients with prior 2nd-line drug use or in poor condition
Revolutionizing MDR-TB Treatment
Outcomes on existing and new MDR-TB treatments
1WHOGlobalReport,2014;2Orenstein,Lancet,2009*;3Johnston,PLoS,2009*;4Diacon,NEJM,2014-P;5Skriponoca,ERJ,2013-P;6Ahuja,PLoS,2012*;7Bonnet,IJTLD,2016;8Diacon,NEJM,2014-A;9Skriponoca,ERJ,2013-A;10Aung,IJTLD,2014;11Piubello,IJTLD,2015;12Kuaban,IJTLD,2014;
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Dawson et al., Lancet, 2015
New Combinations (<=4 drugs) # drugs Drugs Population Duration
(months) Trial
3 PaMZ DS & DR 4 & 6 STAND 3 BPaLzd XDR 6 Nix 3 BPaLzd M/XDR 6 PRACTECAL 3 BPaZ DS 2 (Phase II) NC-005 4 BPaLzdMfx M/XDR 6 PRACTECAL 4 BPaLzdCfz M/XDR 6 PRACTECAL 4 BLzdMfxZ FQ-S MDR 9 endTB 4 DCfzMfxZ FQ-S MDR 9 endTB 4 BPaMZ MDR 2 (Phase II) NC-005
Pa=pretomanid; M=moxifloxacin; Z=pyrazinamide; B=bedaquiline; Lzd=linezolid; Cfz=clofazimine; D=delamanid
New regimens, Shortening # drugs
Drugs Population Duration Trial
5 BLzdLfxZEth (or Hhd,Tzd)
M/XDR 6-9 months NEXT
7 MfxhdCfzEZHhdPthK MfxhdCfzEZ
MDR 16-24 weeks 24
STREAM B
7 BLfxCfzEZHhdPth LfxCfzEZ
MDR 16-24 weeks 24
STREAM C
6 BLfxCfzZHhdK BLfxCfzZ
MDR 8-16 weeks 20
STREAM D
M=moxifloxacin; Z=pyrazinamide; B=bedaquiline; Lzd=linezolid; Cfz=clofzaimine;E=ethambutol; Lfx=levofloxacin; hd=high-dose; Tzd=terizidone; K=kanamycin
Conclusion o Need is large, largely unmet o Optimization
n PZA-use but don’t rely on n Other existing drugs-more is better n DST, though imperfect, is helpful n Duration less sure, shorter works for
some o New drugs may transform number
and duration-for all?
Acknowledgements o Patients o Socios en Salud o Ministerio de Salud-Perú o Bill & Melinda Gates Foundation o NIAID/NIH o Molly Franke, Dylan Tierney,
Mercedes Becerra