Tuberculosis trends & treatment perspectives:

2014Zeena Nackerdien

Worldwide epidemiology, stop TB strategy & other facts (1-3)

DOTS, Directly Observed Treatment, Short-Course; HBC, high-burden countries: Afghanistan, Bangladesh, Brazil, Cambodia, China, Democratic Republic of Congo, Ethiopia, Indonesia, Kenya, Mozambique, Myanmar, India, Nigeria, Pakistan, Philippines, Russian Federation, South Africa, Thailand, Tanzania, Uganda, Vietnam, Zimbabwe; MDR, multidrug –resistant; pts, patients; pops, populations1. World Health Organization. Global Tuberculosis Report 2013 http://www.who.int/tb/publications/global_report/gtbr13_main_text.pdf.2. World Health Organization. The Stop TB Strategy. http://www.who.int/tb/strategy/stop_tb_strategy/en/3. World Health Organization. Tuberculosis fact sheet No. 104 2014 http://www.who.int/mediacentre/factsheets/fs104/en/4. Kaneko T, Cooper C, Mdluli K. Challenges and opportunities in developing novel drugs for TB. Future medicinal chemistry. 2011;3(11):1373-400.

Epidemiology (2012)

Stop TB strategy (2011-2015)

TB 2nd only to HIV/AIDS as single infectious killer

• 8.6 million cases (22% of HBCs account for 80% of cases)

• 940,000 deaths (34% HIV+)• 58% of global cases in • South-East Asia & Western Pacific regions

• 13% HIV/TB cases worldwide• Highest proportion in African region

• Pursue high-quality DOTS expansion & enhancement/health systems strengthening• Address HIV/TB/MDR-TB/ needs of poor & vulnerable pops.• Engage all care providers• Empower pts./communities through partnership• Enable and promote research

• HIV/TB co-infections: 21-34 morelikely to become sick with TB• 11.2 million smear-positive TB cases detected & treated• ~22 million lives saved through DOTS & Stop TB strategy• TB death rates ↓45% (1990-2012)• Affordable 1st-line drugs: $20-$40 for full course (4)

Key 2013 United States TB data (5)

5. United States Centers for Disease Control. New CDC data for TB in the US 2013. Accessed May 2014http://www.cdc.gov/nchhstp/newsroom/2014/WorldTBDay-graphics.html.

TB rates by race/ethnicityProportion of TB cases by national origin

Drug-sensitive TB in immune-competent patients: Initial empirical treatment (4, 6)

Isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin• Four-drug combination for initial treatment of DSTB

Given daily (6-9 monts), cure rates ~85% have been reported if treatment is strictly followed • Works reasonably well, but 1.7 – 1.8 million people still

killed every year• Rise in MDR-TB (TB isolate that is resistant to both

isoniazid and rifampin ) & XDR- TB (MDR + resistance to fluoroquinolone and 1 of the 3 injectable drugs [amikacin, kanamycin, capreomycin])MDR, multi-drug-resistant; XDR, extensively-drug resistant

4. Kaneko T, Cooper C, Mdluli K. Challenges and opportunities in developing novel drugs for TB. Future medicinal chemistry. 2011;3(11):1373-400.6. Multidrug-Resistant Tuberculosis (MDR TB) and Extensively-Drug Resistant (XDR) TB: A Web-Based Seminar presented by the Division of Tuberculosis Elimination Centers for Disease Control and Prevention (CDC) in joint sponsorship with: Francis J. Curry National Tuberculosis Center, Heartland National Tuberculosis Center, Southeastern National Tuberculosis Center, New Jersey Medical School Global Tuberculosis Institute http://www.cdc.gov/tb/publications/webcourseswebinars/mdrandxdrtb/mdrxdr_webinar_final.ppt

Medical costs Financial costs

Medical & financial tolls of MDR-/XDR-TB in the USA (5)

5. United States Centers for Disease Control. New CDC data for TB in the US 2013. Accessed May 2014 http://www.cdc.gov/nchhstp/newsroom/2014/WorldTBDaygraphics.html.

Typical first-line DOTS therapies (4)

• Cell wall (inhibition of NADH-dependent enoyl-ACP reductase)

• AEs include abnormal liver function tests, & peripheral neuropathy

• RNA polymerase

• Most serious AE is hepatotoxicity

• Multiple (including intracellular acidification, decrease of delta pH)

• AEs include joint pain

• Cell wall (inhibition of arabinosyl transferase)

• AEs include optic neuritis, peripheral neuropathy

• Protein synthesis inhibitor

• AEs include fever, rashes, & nephrotoxicity

Rifampicin (8) Pyrazinimide (9)

Ethambutol (10)

Streptomycin (11)

Isoniazid (7)

AEs, adverse events can occur in some patients as collateral or side-effects of an intervention4. Kaneko T, Cooper C, Mdluli K. Challenges and opportunities in developing novel drugs for TB. Future medicinal chemistry. 2011;3(11):1373-400.7. Isoniazid: Wikipedia. Accessed, May 2014 http://en.wikipedia.org/wiki/Isoniazid8. Rifampicin: Wikipedia. Accessed, May 2014 http://en.wikipedia.org/wiki/Rifampicin.

DOTS, d Directly Observed Treatment, Short-Course9. Pyrazinamide: Wikipedia. Accessed, May 2014 http://en.wikipedia.org/wiki/Pyrazinamide.10. Ethambutol: Wikipedia. Accessed, May 2014 http://en.wikipedia.org/wiki/Ethambutol.11. Streptomycin: Wikipedia. Accessed, May 2014 http://en.wikipedia.org/wiki/Streptomycin.

Typical second-line DOTS therapies : drug classes (drugs) & some AEs (4)

• Protein synthesis inhibition: binds to RNA pol. 30s-subunit

• Severe AEs: tinnitus, hearing loss, kidney toxicity, allergy to drug (12)Aminoglycosides,

(kanamycin)• DNA synthesis inhibition: DNA gyrase• AEs include diarrhea, nausea, & FDA black box

warning for increased risk of tendonitis (13)Fluoroquinolones, (ciprofloxacin)

• Cell wall biosynthesis: alanine racemase & D-Ala-D-Ala-ligase

• AEs include dizziness, seizure, somnolence (14)

D-cycloserineAEs, adverse events can occur in some patients as collateral or side-effects of an intervention4. Kaneko T, Cooper C, Mdluli K. Challenges and opportunities in developing novel drugs for TB. Future medicinal chemistry. 2011;3(11):1373-400.12. Kanamycin: Wikipedia; http://en.wikipedia.org/wiki/Kanamycin.13. Ciprofloxacin. Wikipedia: http://en.wikipedia.org/wiki/Ciprofloxacin.14. D-cycloserine (seromycin): Medscape; http://reference.medscape.com/drug/seromycin-cycloserine-342660#4.

• Protein synthesis inhibition: inhibition of translocation

• AEs include nephrotoxicity, 8th cranial auditory vestibular nerve toxicity (15)Polypeptides,

(capreomycin)• Cell wall biosynthesis: inhibition of InhA• Human potential toxicity & AEs: inhibits thyroid

synthesis, drug-drug interactions (16)Thioamides,

(ethionamide)• Thymidylate synthesis inhibition & interference

with iron acquisition• AEs include GI intolerance, hypersensitivity

reactions (17)P-Aminosalicylic acid

DOTS, Directly Observed Treatment, Short-Course; GI, gastrointestinal15. Capreomycin: Wikipedia; http://en.wikipedia.org/wiki/Capreomycin16. Ethionamide: Wikipedia. http://en.wikipedia.org/wiki/Ethionamide.17. p-Aminosalicylic acid. http://reference.medscape.com/drug/paser-aminosalicylic-acid-999678#4.

Management of MDR- & XDR-TB(5,18-19)

AEs, adverse events; HBCs, high-burden countries with multi-drug resistant (MDR) TB: include China, India, Russian Federation, Pakistan, South Africa; WHO, World Health Organization; XDR, extensively-drug resistant5. United States Centers for Disease Control. New CDC data for TB in the US 2013. Accessed May 2014 http://www.cdc.gov/nchhstp/newsroom/2014/WorldTBDaygraphics.html 18. Lange C, Abubakar I, Alffenaar JW, Bothamley G, Caminero JA, Carvalho AC, et al. Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement. The European respiratory journal. 2014 (e-pub).19. TB Alliance. MDR-TB/XDR-TB [cited 2014 May]. http://www.tballiance.org/why/mdr-xdr.php.

• ~450,000 patients worldwide with MDR-TB & XDR-TB

• WHO recommends ≥ 4 antibiotics to which TB is sensitive for a period of 20 months

• Globally, <20% patients with pulmonary MDR-TB/XDR-TB are currently receiving adequate treatment

• Pediatric MDR-TB/XDR-TB: pooled treatment success in studies was 81.7%Severe AEs

• Success compromised by sub-optimal adherence, AEs, & high treatment costs during long course of MDR-/XDR-TB treatment

• Cure: No evidence of failure after completion of recommended national policy, & ≥3 consecutive cultures taken ≥30 days apart, are negative after the intensive phase

HBCs (18)

Treatment

Investigational anti-TB agents (4, 20)

14 vaccine candidates in trials & >35 in discovery/pre-clinical phases

Quinolones (Ph I-III) & Rifamycins (Ph II –III)

Oxazolidinone s (Ph I-II) & diarylquinolines (Ph II-III)

Nitroimidazoles (Ph II – III)

Ethylenediamines, β-lactams,benzothiazinones , Lipo-

uridineAntibiotics (pre-cinical/Ph i)

New antibiotics/vaccines• Inhibition of cell wall biosynthesis (CW)

alone/plus other targets:• Ethylenediamine (SQ109): CW + other

unknown targets ; one of 4 investigational antibiotics targeting CW

• Inhibition of multiple targets• Nitroimidazoles e.g., OPC-67683

• Inhibition of protein synthesis• Oxazolidinones e.g., sutezolid in

development for XDR-TB; linezolid for MDR-TB & XDR-TB

• Inhibition of DNA (DNA gyrase) or RNA synthesis

• Quinolones e.g., gatifloxacin • Rifamycins e.g., rifapentine

• Inhibition of ATP synthesis• Diarylquinolines e.g., TMC207 for DS- &

MDR-TB• Prime, prime/boost, & immunotherapeutic

vaccination strategies (5)4. Kaneko T, Cooper C, Mdluli K. Challenges and opportunities in developing novel drugs for TB. Future medicinal chemistry. 2011;3(11):1373-400.20. Frick M. The TB vaccines pipeline 2013 http://www.tbvi.eu/fileadmin/user_upload/Documenten/News/TBVaccines_pipeline_report_TAG_1July2013.pdf.