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

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Presentation on theme: "New drugs and regimens for TB: 2015 update Scott K. Heysell MD, MPH (no disclosures)"— Presentation transcript:

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

4 Cost of treating a patient with MDR-TB in the United States? $134,000 to $430,000 [for extensively drug-resistant (XDR)-TB]! In European Union  The economic loss in disability adjusted life years was 10 times greater than the treatment cost itself Marks et al. EID 2014 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 Dorman et al. AJRCCM % improvement in 2 month sputum culture conversion! High dose rifamycins may ultimately shorten TB treatment duration 335 patients: TB Trials Consortium

7 Weekly moxifloxacin and rifapentine in the continuation phase RIFAQUIN trial Jindani et al. NEJM 2014  Equivalent  Inferior

8 Smythe et al. AAC 2013 AUC ↓~14.3% following multiple 400-mg daily doses of gatifloxacin 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? All “susceptible” by conventional DST 400mg 600mg 800mg

9 515 patients  84.5% cure! 5.6% death Remainder with default or relapse Aung et al, Int J Tuberc Lung Dis months: high-dose gatifloxacin, EMB, PZA, clofazimine plus first 4+ months: KM, PTO, high-dose INH The ‘Bangladesh Regimen’ for MDR-TB

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

11 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 With permission, Mymensingh

12 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* Heysell et al. Tuberc Respir Dis 2015 We use linezolid (with caution) in MDR-TB patients with additional resistance to fluoroquinolones and/or injectable agents (pre-XDR and XDR-TB) * Thanks to everyone at !

13 bedaquiline sutezolid delamanid pretomanid

14 ▪Drug-induced phospholipidosis (like amiodorone) in organs and other tissues Safety concerns with bedaquiline metabolized in liver CYP3A4 ▪can’t give with rifampin as will significantly lower bedaquiline concentrations; protease inhibitors, macrolides etc will increase bedaquiline concentrations half life 24 hours, terminal elimination half life of 5.5 months ▪Drug-related hepatic disorders (8.8% bedaquiline v. 1.9% placebo) ▪ Not to be used together with delaminid (both with QT prolongation) 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

15 Cure rates at 120 weeks: bedaquiline group 58% placebo group 32% (p = 0.003) Diacon et al. NEJM 2014 *Death 10/79 (13%) bedaquiline v. 2/81 2% in placebo (p=0.02) *QTc increase more common with bedaquiline Bedaquiline + optimized background regimen  faster time to culture conversion and higher rate of 120 week cure

16 bedaquiline sutezolid delamanid pretomanid

17 Gler et al. NEJM 2012 Delamanid with improved 2 month culture conversion QT prolongation more common than with placebo ▪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

18 2 mo delamanid Favorable outcome 55% Cure 48% Death 8.3% 6 mo delamanid Favorable outcome 74.5% Cure 57.3% Death 1.0% 6 months of delamanid is more efficacious and tolerable 421 patients

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 Metformin: Enhances killing of M. tuberculosis in the laboratory In Virginia, what you are doing for diabetes may be most important *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 Singhal et al, Sci Trans Med 2014

21 ▪Clofazimine and the ‘Bangladesh regimen’ may be here to stay for MDR-TB  await STREAM trial ▪High dose Rifapentine planned for treatment shortening in DS-TB ▪Rifapentine/ Moxifloxacin a future option for once weekly dosing in continuation phase? ▪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 Summary


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