Shortening Tuberculosis Treatment Recent advances

1
Shortening TuberculosisTreatment Recent
advances

• Dr. M S Jawahar
• Deputy Director (Sr. Gr.)
• Tuberculosis Research Centre
• Chennai

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Tuberculosis

• Ancient disease
• At least 4000 years
• ? From cattle when they were domesticated

3
Rene Laennec
Ramanujam
John Keats
Vivien Leigh
Percy B Shelley
Samuel Johnson
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Victims of a dread disease

• Sir Walter Scott Author 61
• Srinivasan Ramanujam Mathematician 32
• Rene Laennec Physician 45
• Percy Bysshe Shelley Poet 30
• John Keats Poet 27
• Emily Bronte Poet 29
• Charlotte Bronte Author 39
• Francois Chopin Musician 39
• Robert Louis Stevenson Author 44
• Mohammed Ali Jinnah Politician 72
• George Orwell Author 47
• Vivien Leigh Actress 53

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Selman Waksman

• Discovered streptomycin 1944
• Nobel Prize for physiology /medicine - 1952

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TB treatment

• Currently recommended treatment regimens are the
  results of numerous clinical trials in many parts
  of the world
• Many of the principles of TB treatment were
  evolved from research at TRC, Chennai
• Efficacy of domiciliary treatment
• Efficacy of short-course chemotherapy
• Efficacy of intermittent treatment
• Necessity of supervised treatment (DOTS)

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Evolution of TB treatment

• Monotherapy (Streptomycin)
• 2 drugs 1950s duration 18-24 months
• 3 drugs 1960s duration 12-18 months
• 3 drugs late 1960s duration 9 months
• 4 drugs 1970s duration 6 months

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Treatment for TB

• Duration 6 months
• Number of drugs 4

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Bactericidal Sterilising drug actions
Isoniazid, Strptomycin Rifampicin (Bactericidal)
Rapidly multiplying
Dormant
Rifampicin, Isoniazid Pyrazinamide (Sterilising)
M Tb
Slowly multiplying
Time
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• Shortening short course chemotherapy
• the TRC quinolone experience

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• Current TB treatment is 6 months
• Since early 1970s
• Shortening TB treatment has many advantages
  (patients providers)
• Priority research agenda for TB control

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Regimens of 3 - 4 months for smear pulm. TB
Definition less stringent
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Regimens
Dose in mg O Ofloxacin 400/600 H
Isoniazid 300/600 R Rifampicin 450/600
Z Pyrazinamide 1500
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1 2 3 4
5 6
months
Intensive phase Continuation
phase
INH
RIF
PZA
EMB
INH
RIF
PZA
OFX
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Sputum culture conversion with treatment(360
patients with drug susceptible TB) Ind J Tub
2002 49 27-38
98
97
94
92
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Response at end of treatment (360 patients with
drug susceptible TB) Ind J Tub 2002 49 27-38
1
1
1
1
94
96
97
92
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Relapse after treatment (up to 24 months) (341
patients with drug susceptible TB)Ind J Tub
2002 49 27-38
18

• Daily dosing difficult for DOT
• RNTCP geared for thrice-weekly treatment
• Previous experience has shown that intermittent
  regimens can be as effective as daily regimens

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Intermittent quinolone regimens

• Trials at TRC with 4-month thrice-weekly
  ofloxacin, gatifloxacin or moxifloxacin regimens
  had high relapse rates
• Trials aborted midway

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Newer quinolones

• TRC ofloxacin study generated global interest in
  quinolones in TB treatment
• Invitro animal studies newer quinolones
  (gatifloxacin/ moxifloxacin) more potent than
  ofloxacin against M. tuberculosis
• Both bactericidal sterilising activities
• Safety profile good in short-term Rx

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TRC Study 24Randomised clinical trial to study
the efficacy and tolerability of 3- 4-month
regimens containing moxifloxacin in the treatment
of patients with sputum smear culture positive
pulmonary tuberculosis
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Mean log CFUs from lung homogenates (mice)
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Regimens
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Other 4-month quinolone regimen studies
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Expected timelines towards approval of candidate
drugs currently in clinical stage of
development (Sources Global TB Alliance Annual
report 2004-2005StopTBPartnership Working Group
on New Drugs for TB. Strategic Plan 2006-2015)