TB – Yesterday, Today and
Tomorrow
Jerrold J. Ellner MD
Boston University
Sept 2013
“If the number of victims that a disease
claims is the measure of its
significance, then all diseases,
particularly the most dreaded
infectious diseases such as bubonic
plague, Asiatic cholera, etc., must rank
far behind tuberculosis.”
- Robert Koch, 1882
Short History of TB
• 1882 – Koch discovers tubercle bacillus*
• 1907 – von Pirquet adapts Koch’s tuberculin as
diagnostic test
• 1919 – Calmette & Guerin produce BCG vaccine
• 1943 – Schatz and Waksman discover
streptomycin*
• 1948 – BMRC trial of streptomycin vs. bedrest
• 1952 – development of INH
• 1966 – development of rifampicin
• 1978 – ‘short-course’ TB treatment (6 months)
• 1990s- DOTS strategy
Global TB 2010
• 8.8 million new cases – 1.1 HIV
• 1.5 million deaths – 0.35 HIV
• 0.65 MDR – 10% XDR = 3.4% new;
20% retreatment cases
WHO Reports. 2011
TB Cases
Natural History of TB
50%
Reexpos
5% (40%)
Reexpos
5% (2-10%/y)
Lancet Inf Dis 2008;8:601-11
DIAGNOSIS OF ACTIVE TB
TB diagnostics, 1882
TB diagnostics, 2010
AFB (acid fast bacilli) smear
AFB (shown in red) are tubercle bacilli
Proportion of Patients with Pulmonary
TB with Positive AFB Smears
70
60
HIV uninf
AFB positivity in
TB patients
Early HIV
50
40
Late HIV
30
20
10
0
Similar for “classic” RUL infiltrate
MGIT
LJ
PCR
FM ZN
1+
101
102
103
104
2+
3+
105
4+
106
107
E-MTD sensitivity >95% smear (+); 75-90%
smear (-)
Amplicor sensitivity >95% smear (+); 60-70%
smear (-)
11
MMWR Jan 16, 2009
NEJM. – published on-line Sept
Xpert – MTB-RIF
• One sample – 98% smear pos, 73%
smear neg
• Three samples – 100% smear pos,
90% smear neg
• Specificity - 99%
• Sensitivity MDR-TB – 97%
GeneXpert rolled out as first-line diagnostic for
TB in South Africa - 31 March 2011
"If a minister can do it, it can’t be that hard," said South
African Health Minister Aaron Moatsoaledi,
Demonstrating GeneXpert test for TB
GeneXpert
Xpert
MTB/RIF
5
16
20
80
Samples per shift
500-1000
IGRA v TST
• Mtb specific antigens (ESAT-6, CFP10, TB 7-7)
• Higher specificity, correlation with
exposure, less cross-reactivity BCG,
non tuberculosis mycobacteria
• One visit dx
• TST not quality controlled
application, reading
TST v IGRA
• Variable cut-point, risk stratification
• Strong epi basis
• Standard definitions, TST
conversion, boosting
• ? Less variability near cutpoint
• Preferable for annual screening
• Less expensive
Diagnosis LTBI
• TST first:
if negative IGRA:
immunocompromised, high risk,
?active TB
if positive IGRA:
BCG vaccinated, ?NTM
Nature Rev Micro. 2009
393 Trancripts TB v LTBI v HC
Nature. 2010
Estimated HIV-TB Co-infection Prevalence, 2000
Rate per 100 000
<5
5 - 9.9
10 - 99
100 - 999
1000 - 4999
5000 or more
No estimate
From presentation made by: Paul Nunn, WHO, Geneva,
Durban 2002
Accuracy of Determine TB-LAM, by CD4
96.6
98.3
63.9
%
Sensitivity 69% for CD4 <50
Sensitivity 53% for CD4 50-100
Rapid Dx TB-HIV
AFB Smear Neg PTB
• Xpert sens 62%
• LAM sens 45%
• LAM plus/then Xpert sens 79%
Optimal timing of antiretroviral therapy
in adults with untreated HIV-infection and new
TB
ART started within 2 weeks
of TB tx improves survival
in PTB patients with
Adv. immunosupression;
increased risk of IRIS
Why is TB treatment duration so long?
Hypothetical Model of TB Chemotherapy
D. Mitchison
# bacilli
anatomic/metabolic populns of bacilli cavitary TB
A
A: rapidly multiplying, INH>RIF>EMB
B: slowly multiplying, PZA>RIF>INH
C: sporadically multiplying, RIF>INH
B
C
1
2
3
4
# months of therapy
5
6
Drug-susceptible TB: strategies for
shortening duration of treatment
required for cure
Optimize the use of the drugs
in the regimen (RIF)
•RIF at higher dose
•RPT instead of RIF
Replace EMB (low potency)
with a more active drug (e.g. FQ)
EMB
PZA
RIF
RIF
INH
INH
1
2
3
Treatment month
4
5
6
Bedaquiline
(‘Sirturo’, from Johnson & Johnson)
Addition of bedaquiline (vs. placebo)
to a 5-drug MDR-TB regimen resulted
in:
• Faster culture conversion
• Higher sputum culture conversion
rate at 24 weeks (78.8% vs. 57.6%)
• Prevention of acquired resistance to
other background drugs
108
From Johnson & Johnson
#: number of subjects at risk (i.e., culture positive subjects ongoing in the trial at the corresponding time point)
Note: The intersection of horizontal dotted line and each treatment arm represents the median time to sputum
culture conversion.
LINEZOLID in XDR-TB:
Kaplan–Meier Curves for Culture Conversion According to Time since
Randomization.
NEJM. 2012
Lee M et al. N Engl J Med 2012;367:15081518.
PRECLINICAL DEVELOPMENT
TBA-354
Nitroimidazoles
TB Alliance, U Auckland, U Illinois
CPZEN-45
Caprazene nucleoside
MCRF, Lily TBDDI, NIAID, IDRI
Quinolone DC – 159a
Fluoroquinolone Antibiotics
JATA, Daiichi-Sankyo
Pharmaceutical
SQ609
Dipiperidines
Sequella
SQ641
Capuramycins
Sequella
BTZ043
Benzothiazinones
New Medicines For Tuberculosis
(NIM4TB)
Q201 – Novel anti – TB agent
Imidazopyridine
Quro Science, Inc.
PHASE I
AZD587
Oxazolidinone
Astrazeneca
PHASE II
PHASE III
PA – 824
Nitroimidazoloxazine
TB Alliance
Gatifloxacin
Fluoroquinolone
WHO/TDR
PNU – 100480 (Sutezolid)
Oxazolidinone
Pfizer
Moxifloxacin
Fluoroquinolone
TB Alliance
TMC207 (Bedaquiline)
for MDR- TB
Diarylquinoline
Tibotec BVBA
OPC-67683 (Delamanid)
Nitrodihydroimidazooxazole
Otsuka Pharmaceutical
SQ109
Ethylenediamines
Sequella, NIH
TMC207 (Bedaquiline)for
DS – TB
Diarylquinoline
TB Alliance, Janssen
Rifapentine (TBTC study
29)
Rifamycin
CDC, Sanofi-aventis