1. New drugs and regimens for TB: 2015 update
Scott K. Heysell MD, MPH
(no disclosures)

2. 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

3. + + + + + + ethambutol pyrazinamide kanamycin (8+ months) minimum
who.int/tb/challenges
minimum
20 months! + +
ofloxacin
cycloserine
PAS granules + +
+ ?
truvada
pyridoxine
efavirenz
TMP/sulfa

4. 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
Multiple cases of MDR can ‘break the bank’ or a single case in smaller state, or more realistically decreased total cases but increased proportion of MDR could significantly change appropriations over years. Exceeds the lifetime cost to treat a patient for breast cancer.
Diel et al. Euro Respir J 2013

5. 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)

6. High dose rifamycins may ultimately shorten TB treatment duration
335 patients: TB Trials Consortium
335 patients in TBTC sites worldwide, most in the USA
13-26% improvement in 2 month sputum culture conversion!
Dorman et al. AJRCCM 2015

7. Weekly moxifloxacin and rifapentine in the continuation phase
RIFAQUIN trial
Equivalent
827 patients RCT, replacing isoniazid with Rifapentine x 1 month and Moxi x 2 months; then 4 months Moxi/Rifapentine dosed once weekly; or 2 months Moxi/Rifapentine dosed twice weekly . REMOX await results, moxi for ethambutol or isoniazid in order to shorten treatment duration to 4 months. RPT in reg 1 was 900 mg tiw, reg mg weekly. 730 people, HIV infected 28% (not on ARVs, median CD4 312). Seventeen percent in the two-month arm reached an endpoint of treatment failure, relapse or death, compared to 5% in the standard-of-care arm, and when loss to follow-up and treatment changes for reason other than failure were included, 28% in the two-month arm reached an endpoint, compared to 14% in the standard-of-care arm.
Inferior
Jindani et al. NEJM 2014

8. Importance of pharmacokinetics and M. tuberculosis MIC?
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
Initially single dose study of gatifloxacin with RHZ found increase in gatifloxacin exposure. Opposite effect after multiple daily doses.
600mg
800mg
All “susceptible” by conventional DST
Smythe et al. AAC 2013

9. The ‘Bangladesh Regimen’ for MDR-TB
9+ months:
high-dose gatifloxacin, EMB, PZA, clofazimine
plus
first 4+ months:
KM, PTO, high-dose INH
Include Mymensingh photo? Criticisms. No effect of clofazimine in 14 day early bactericidal studies, alone or in combination. Add CFZ from RCT in China! 94% with skin discoloration in China, mention mechanism of dye riminophenazine
515 patients
84.5% cure!
5.6% death
Remainder with default or relapse
Aung et al, Int J Tuberc Lung Dis 2014

10. Father Damien ultimately canonized in 1995: when asked what miracle he had performed, Mother Theresa answered, “Damien himself is a miracle.”
Father Damien. “Leper Colony” in Molokai. “The scenery is magnificent.”

11. ▪Observational study, many patients were excluded ▪No HIV
With permission, Mymensingh
Now large multicenter international RCT comparing to current WHO standard of care (STREAM trial) outside of Bangladesh
Photo Mymensingh: food, careful attention occupational training, management of side effects,
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

12. 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 ( )
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*
Pharmacokinetics probably important
*Thanks to everyone at !
Heysell et al. Tuberc Respir Dis 2015

13. pretomanid
delamanid
sutezolid
bedaquiline

14. 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)
One clinical trial in African patients showed no benefit. Lower plasma concentrations in patients of African decent. Check K, Ca, Mg, Phos
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)

15. 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)
5/10 deaths from TB. All had no culture conversion or reversion of positivity. Overall low rate of culture conversion, but also low rate of death. QTc significantly prolonged, but no arrhythmias reported and blinded reviewer said deaths not related to study drug. 9 BDQ patients after drug was stopped (median 49 weeks after stopped). Death by MVC in one patient for example. Recommended ca, mg, k, phos, ecgs mention stockouts.
*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

16. pretomanid
delamanid
sutezolid
bedaquiline

17. 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
No CYP 450 interaction. Albumin in plasma. Contraindicated with serum albumin <2.8. Adding to RZE in murine model much greater effect than RIZE alone.
Favourable outcomes were observed in 143 (74.5%) out of 192 patients who received delamanid for ≥6 months, compared to 126 (55%) out of 229 patients who received delamanid for ≤2 months. Mortality was reduced to 1.0% among those receiving long-term delamanid versus short-term/no delamanid (8.3%; p<0.001). Treatment benefit was also seen among patients with extensively drug-resistant TB
Gler et al. NEJM 2012

18. 6 months of delamanid is more efficacious and tolerable
421 patients
No deaths in XDR patients treated with long-term delamanid (56 total XDR 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%

19. 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

20. 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

21. 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