Transcript New Drugs and Regimens for TB: 2015 Update

New drugs and regimens for TB:
2015 update
Scott K. Heysell MD, MPH
(no disclosures)
Why do we need new drugs/ regimens?
▪Isoniazid and pyrazinamide remain some of the most toxic
antibiotics prescribed for infectious disease
-decrease toxicity
▪Even in U.S., completion of therapy in 12 months ~ 90% …
but completion in 6 months is actually the minority of DS-TB
-shorten therapy
▪Multidrug-resistant TB, or intolerance to first-line drugs
-improve efficacy
ethambutol
kanamycin (8+ months)
pyrazinamide
+
+
who.int/tb/challenges
+
+
ofloxacin
PAS granules
cycloserine
+
+
+ ?
pyridoxine
minimum
20 months!
truvada
efavirenz
TMP/sulfa
Cost of treating a patient with MDR-TB in the United States?
$134,000 to $430,000 [for extensively drug-resistant (XDR)-TB]!
Marks et al. EID 2014
In European Union
The economic loss in disability adjusted life years was
10 times greater than the treatment cost itself
Diel et al. Euro Respir J 2013
Retooling conventional TB drugs or other non-TB drugs
▪Higher dose or
later generation
fluoroquinolones
(eg. moxifloxacin)
▪clofazimine
▪linezolid
▪High-dose rifampin or
rifapentine
lepromatous leprosy
(at U of Virginia)
High dose rifamycins may ultimately
shorten TB treatment duration
335 patients: TB Trials Consortium
13-26% improvement in 2 month
sputum culture conversion!
Dorman et al. AJRCCM 2015
Weekly moxifloxacin and rifapentine in the continuation phase
RIFAQUIN trial
Equivalent
Inferior
Jindani et al. NEJM 2014
REMox and OFLOTUB failed in replacing ethambutol or isoniazid
with fluoroquinolone to shorten tx to 4 months total:
Importance of pharmacokinetics and M. tuberculosis MIC?
AUC ↓~14.3%
following multiple
400-mg daily doses
of gatifloxacin
400mg
600mg
800mg
All “susceptible” by conventional DST
Smythe et al. AAC 2013
The ‘Bangladesh Regimen’ for MDR-TB
9+ months:
high-dose gatifloxacin,
EMB, PZA, clofazimine
plus
first 4+ months:
KM, PTO, high-dose INH
515 patients
84.5% cure!
5.6% death
Remainder with default or relapse
Aung et al, Int J Tuberc Lung Dis 2014
Father Damien ultimately
canonized in 1995: when asked
what miracle he had performed,
Mother Theresa answered,
“Damien himself is a miracle.”
With permission, Mymensingh
Criticisms of ‘Bangladesh’ regimen, reasons for larger multinational trial:
▪Observational study, many patients were excluded
▪No HIV
▪Treated in Damien Foundation centers with consequent attention to nutrition,
careful management of side effects, occupational training and family support
We use linezolid (with caution) in MDR-TB patients with additional
resistance to fluoroquinolones and/or injectable agents
(pre-XDR and XDR-TB)
5 years (2009-2014)
10 cases of MDR-TB in Virginia
if susceptible to fluoroquinolone then cure rate 6/7*
3 cases were resistant to fluoroquinolone or all injectable agents  pre-XDR
All 3 pre-XDR received linezolid
2 were given 600 mg daily and were cured*
*Thanks to everyone at
!
Heysell et al. Tuberc Respir Dis 2015
pretomanid
delamanid
sutezolid
bedaquiline
Safety concerns with bedaquiline
half life 24 hours, terminal elimination half life of 5.5 months
▪Drug-induced phospholipidosis (like amiodorone) in organs and other tissues
metabolized in liver CYP3A4
▪can’t give with rifampin as will significantly lower bedaquiline concentrations;
protease inhibitors, macrolides etc will increase bedaquiline concentrations
▪Drug-related hepatic disorders (8.8% bedaquiline v. 1.9% placebo)
prolongs the QTc
▪ the mean increase in QTc was greater for patients taking bedaquiline and
clofazimine (32-ms increase) than for bedaquiline alone (12.3 ms). No TdP
▪ Not to be used together with delaminid (both with QT prolongation)
Bedaquiline + optimized background regimen faster time
to culture conversion and higher rate of 120 week cure
Cure rates at 120 weeks:
bedaquiline group 58%
placebo group 32%
(p = 0.003)
*Death 10/79 (13%) bedaquiline v. 2/81 2% in placebo
(p=0.02)
*QTc increase more common with bedaquiline
Diacon et al. NEJM 2014
pretomanid
delamanid
sutezolid
bedaquiline
Delamanid
▪Novel nitro-dihydroimidazo-oxazole derivative
▪More M. tuberculosis
specific minimal drug
interactions
▪High volume of distribution
▪Dose dependent activity in
vitro similar to rifampin
Delamanid with improved
2 month culture conversion
QT prolongation more common
than with placebo
Gler et al. NEJM 2012
6 months of delamanid is more efficacious and tolerable
421 patients
2 mo delamanid
Favorable outcome 55%
Cure 48%
Death 8.3%
6 mo delamanid
Favorable outcome 74.5%
Cure 57.3%
Death 1.0%
How new drugs are currently being used:
we need a new regimen
First compassionate use delamanid in Europe (pediatric XDR-TB)
Esposito et al. ERJ 2014
In Virginia, what you are doing for diabetes may be most important
Singhal et al, Sci Trans Med 2014
Metformin:
Enhances killing of M. tuberculosis
in the laboratory
*HgbA1c to rule-in or rule-out diabetes and
refer to care: don’t rely on self-report
*Early therapeutic drug monitoring for
diabetics
*Educational flip-chart
Summary
▪High dose Rifapentine planned for treatment shortening in DS-TB
▪Rifapentine/ Moxifloxacin a future option for once weekly dosing
in continuation phase?
▪Clofazimine and the ‘Bangladesh regimen’ may be here to stay for
MDR-TB await STREAM trial
▪Get to know Bedaquiline and Delamanid but not ready for prime-time
in the U.S.
▪Let’s continue to prioritize diabetes here in Virginia