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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Reference

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

12

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

30

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