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 pyrazinamide
kanamycin (8+ months)

+ +
who.int/tb/challenges

minimum
+ + 20 months!

ofloxacin cycloserine PAS granules

+ ? + +
pyridoxine 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
lepromatous leprosy
▪High-dose rifampin or (at U of Virginia)
rifapentine
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-dihydro-
imidazo-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 6 mo delamanid
Favorable outcome 55% Favorable outcome 74.5%
Cure 48% Cure 57.3%
Death 8.3% 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