Jerrold J. Ellner MD

Boston University

Sept 2013

TB – Yesterday, Today and Tomorrow

“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

Lancet Inf Dis 2008;8:601-11

50%5% (40%)

5% (2-10%/y)

Re-exposRe-expos

Re-exposRe-expos

                                    

TB diagnostics, 1882 TB diagnostics, 2010

DIAGNOSIS OF ACTIVE TB

AFB (acid fast bacilli) smear

AFB (shown in red) are tubercle bacilli

Proportion of Patients with PulmonaryTB with Positive AFB Smears

0

10

20

30

40

50

60

70AFB positivity in TB patients

Similar for “classic” RUL infiltrate

Late HIV

Early HIV

HIV uninf

11

MGIT LJ PCR FM ZN

102 104 105 106 107103101

1+ 2+ 3+ 4+

E-MTD sensitivity >95% smear (+); 75-90% smear (-)Amplicor sensitivity >95% smear (+); 60-70% smear (-)

MMWR Jan 16, 2009

NEJM. – published on-line Sept 1, 2010

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

16

5 20 80 500-1000Samples per shift

GeneXpert

Xpert MTB/RIF

IGRA v TST

• Mtb specific antigens (ESAT-6, CFP-10, 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

10 - 99

100 - 999

1000 - 4999

< 5

5 - 9.9

5000 or more

No estimate

Rate per 100 000

From presentation made by: Paul Nunn, WHO, Geneva, Durban 2002

Accuracy of Determine TB-LAM, by CD4

63.9

96.6 98.3

%

Sensitivity 69% for CD4 <50Sensitivity 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?

A

B

C

Hypothetical Model of TB Chemotherapy

anatomic/metabolic populns of bacilli cavitary TB

# b

acill

i

# months of therapy

A: rapidly multiplying, INH>RIF>EMBB: slowly multiplying, PZA>RIF>INHC: sporadically multiplying, RIF>INH

D. Mitchison

1 2 3 4 5 6

Drug-susceptible TB: strategies for shortening duration of treatment

required for cure

1 2 3 4 5 6

EMB

PZA

RIFRIF

INHINH

Treatment month

Optimize the use of the drugs in the regimen (RIF)•RIF at higher dose•RPT instead of RIFReplace EMB (low potency) with a more active drug (e.g. FQ)

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

From Johnson & Johnson

Kaplan–Meier Curves for Culture Conversion According to Time since Randomization.

Lee M et al. N Engl J Med 2012;367:1508-1518.

LINEZOLID in XDR-TB:

NEJM. 2012

PRECLINICAL DEVELOPMENT PHASE I PHASE II PHASE III

TBA-354NitroimidazolesTB Alliance, U Auckland, U Illinois

AZD587 OxazolidinoneAstrazeneca

PA – 824NitroimidazoloxazineTB Alliance

GatifloxacinFluoroquinoloneWHO/TDR

CPZEN-45Caprazene nucleosideMCRF, Lily TBDDI, NIAID, IDRI

PNU – 100480 (Sutezolid)OxazolidinonePfizer

MoxifloxacinFluoroquinoloneTB Alliance

Quinolone DC – 159aFluoroquinolone AntibioticsJATA, Daiichi-Sankyo Pharmaceutical

TMC207 (Bedaquiline)for MDR- TBDiarylquinolineTibotec BVBA

OPC-67683 (Delamanid)Nitrodihydroimidazo-oxazoleOtsuka PharmaceuticalSQ609

DipiperidinesSequella SQ109

EthylenediaminesSequella, NIH

SQ641CapuramycinsSequella

TMC207 (Bedaquiline)for DS – TBDiarylquinolineTB Alliance, Janssen

BTZ043BenzothiazinonesNew Medicines For Tuberculosis(NIM4TB)

Rifapentine (TBTC study 29)RifamycinCDC, Sanofi-aventis

Q201 – Novel anti – TB agentImidazopyridineQuro Science, Inc.