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Are TB, malaria and Anti-Microbial Resistance declining fast enough to

meet SDGs by 2030?
Tuesday 30 August 2016

Drug-Resistant Tuberculosis can be Avoided and

Cured.
Current Situation and possible Future
Prof. Jose A. Caminero, MD
Multi-Drug-Resistant Unit Coordinator
International Union against Tuberculosis and Lung Disease (The Union)

Mycobacterium tuberculosis Resistance

Definitions

Multidrug-resistance Tuberculosis (MDR-TB)

Mycobacterium tuberculosis resistant to, at least, Isoniazide
and Rifampicin, the two best anti-TB drugs

Extensively-drug-resistance TB (XDR-TB)
MDR-TB plus resistance to any Fluoroquinolone and, at
least, one second line drug injectable (kanamycin,
amikacin and capreomycin), the two best second line drugs
available

The Threat of Drug-Resistant Tuberculosis

(DR-TB)
A new epidemic..

- Drug resistance (DR-TB) in TB was described and explained in 1945-1955

- Until the end of the 1980s DR-TB Cases was only managed in very
few reference centres in high-income countries
-In the 1970-1990s, with widespread use of rifampicin and poor
case management, increasing levels of resistance were created in
some countries/regions
some isolated XDR-TB cases started to appear
-The increasing severity of the MDR-TB situation is relatively recent
(< 15-20 years)

WHO. The global situation 2014

All forms of TB
HIV-associated
TB
Multidrugresistant TB

Estimated incidence,
2014

Estimated number of
deaths, 2014

9.6 million

1.1 million*

(9.110.0 million)

(1.01.3 million)

1.2 million

390,000

(1.01.3 million)

(350,000430,000)

480,000

190,000

(360,000600,000)

(120,000260,000)

Source: WHO Global Tuberculosis Report 2015

* Excluding deaths attributed to HIV/TB

MDR-TB: 3% of new TB cases globally

Highest % in the former USSR

countries

India, China, Russia, Pakistan and Ukraine

have 62% of all MDR-TB cases

Ref: Global TB Control Report 2015

Percentage of new TB cases with MDR-TB

Global Epidemic MDR-TB Situation

WHO. Drug-Resistant TB. Supplement Global TB Repo

In 2013, more than 50% of New cases of MDRTB were among people never before treated for
TB, highlighting the importance of
Transmission and the lack of appropriate
Infection Control Measures, particularly at
Community level

MDR-TB in the World Uncontrolled Epidem

M. tuberculosis Resistance
-

In TB, the origin of drug resistance has been the poor

case management, individual or collective, of drug
sensitive TB cases

This bad management is still the origin of around 50%

TB resistant cases.

The rest 50% is because active transmission of DRTB strains in the community

DR-TB can be Avoided (1)

The first priority to fight against
MDR/XDR-TB is to Strengthen the
National Tuberculosis Programmes
(NTP) with good management of
susceptible TB cases (DOTS)

DR-TB can be Avoided (2)

But currently is also a Priority

the Early Detection and Cure
the MDR/XDR-TB cases,
to try to avoid the
Transmision

The 90-90-90 targets proposed for

the Global Plan to Stop TB:

1. Finding at least 90% of all TB cases in the

population
and put as many as possible
of these on effective treatment.
2.Making a special effort to reach at least
90% of the most
vulnerable, underserved
or at risk populations (Key
populations
for TB) in the countries through
screening and active case finding

3.Reaching at least 90% treatment success

DR-TB can be Avoided (1)

The first priority to fight against
MDR/XDR-TB must be to Strengthen the
National Tuberculosis Programmes
(NTP) with good management of
susceptible TB cases (DOTS)

Reaching the "missed" cases early is crucial

(~3.6 million not diagnosed or reported)

Share of total missed

cases

9.6 million
estimated

6 million notified

10 countries account for

75%
(2.7 million) of the
estimated missed cases
globally

Estimated incidence
Global notifications

Ref: Global TB Control

Indonesia + India:
1.2 million missed people

Source: WHO Global Tuberculosis

DR-TB can be Avoided (1)

-

The first priority to fight against MDR/XDR-TB must be to Strengthen

the National Tuberculosis Programmes (NTP) with good management of
susceptible TB cases (DOTS)

Currently, despite the global cure rate is near 90%, the rate of detection
is only around 65%.

Therefore, we have still a long way to achieve a Good management of

the susceptible initial case to avoid the generation of DR-TB cases

The 90-90-90 targets proposed for

the Global Plan to Stop TB:

1. Finding at least 90% of all TB cases in the

population
and put as many as possible
of these on effective treatment.
2.Making a special effort to reach at least
90% of the most
vulnerable, underserved
or at risk populations (Key
populations
for TB) in the countries through
screening and active case finding

3.Reaching at least 90% treatment success

DR-TB can be Avoided (2)

But currently is also a Priority

the Early Detection and Cure
the MDR/XDR-TB cases,
to try to avoid the
Transmision

MDR-TB remains a public health crisis

Case Detection: 25%

Cured Rate: 50%

DR-TB can be Avoided (2)

- The Second priority to fight against MDR/XDR-TB must be to
Detect 90% of the MDR-TB Cases and to Cure 90% of them
- However, the rate of Detection is only 25% and the rate of
Cure cases 50% Clear Failure
- Therefore, just Individual benefit can be achieved, but the
Epidemiological (Community) impact is Minimum

DR-TB can be Avoided (2)

Therefore, to Achieve a Control of the DR-TB Epidemic,

it is very urgent to Increase notably the Rate of
Detection of TB cases (susceptible and DR-TB) and the
Rate of Cured cases of DR-TB

How can be Increased the TB and MDR-TB

Detection ?
1. Rapid (Molecular) and very sensitive Drug
Susceptibility Test for all the patients with
Suspect of TB GeneXpert Ultra or Similar
2. To Improve the Health Coverage of all the
Patients To Strength the Health System
(totally Free)

How can be Increased the Successful

Outcome in the MDR-TB Treatment ?

1. Shorter MDR-TB Regimens and better

tolerated
2. Possibility to Incorporate New Drugs:
Linezolid, Bedaquiline, Delamanid,
Pretomanid, etc

To Cure > 90% MDR-TB

Cases

With the current MDR-TB

regimens the highest
Successful Outcome is
around 50-60%

Outcomes of MDR-TB treatment

MDR-TB cohorts 2007-2012, global

Outcomes of XDR-TB treatment

XDR-TB cohorts 2012, by WHO Region*

*number of cases observed shown next to the bars

Am J Respir Crit Care Med Vol 182. pp 684692, 2010

- Bangladesh: 427 MDR-TB (1997-2007) not receiving previously SLD

- 206 (4 Kn-Pth-H-Gx-Cfz-E-Z / 5 Gx-Cfz-E-Z) CURE 87.9%
(relapse-free) (95% CI, 82.791.6)
- Major adverse drug reactions were infrequent and manageable.
- Compared with the 221 patients treated with regimens based on
ofloxacin and commonly prothionamide throughout, the
hazard ratio of any adverse outcome was 0.39 (95%
confidence
interval, 0.260.59).

TB in
on on
under

enefit
dwide;
sening
riately

mized
n the
ective

/tb

which is tolerable have been ongoing for several

resistant-TB,
regardless
of patient age or HIV status
years through
various studies.
FEATURESOFTHE
Recently,
a
standardized
treatment
regimen
Monitoring for effectiveness, harms and relapse will
lasting less than 12 months has been used in a
SHORTERMDR-TB
be needed.
Patient-centred
and
social support
number of
countries (see map).care
It has
shown
Standardized shorter
results
in selected
patients
will bepromising
essential
to
enableMDR-TB
patient
adherence drugs and a treatment
Based on data from these studies, WHO updated
Indicated conditionall
Programmatic
is feasible
in most
its treatmentuse
guidelines
for drug-resistant
TBsettings
in
resistant-TB, regardles
May 2016 and included a recommendation on
Monitoring for effectiv
worldwide
the use of the shorter MDR-TB regimen under
be needed. Patient-ce
Lowered
costs
and
reduced
patient
loss
expected
specific conditions.
will be essential to en
nd
This new
recommendation
is expected
to benefit
Programmatic use is fe
Exclusion
criteria:
2 line
drug resistance,
the majority of MDR-TB patients worldwide;
worldwide
extrapulmonary
disease
and
pregnancy.
however, there are serious risks for worsening
Lowered costs and red
resistance if the regimen is used inappropriately
Exclusion criteria: 2nd l
Countries usingthe shorter MDR-TBregimen
BACKGROUND (e.g. in XDR-TB patients).
extrapulmonary disea
(excludingclinical trial sites)
Multidrug-resistant tuberculosis
(MDR-TB) is ongoing
a
WHO encourages
and future randomized
public health crisis and a global health security
controlled clinical trials to strengthen the
REGIMENCOMPO
risk carrying grave consequences for those
evidence base for shorter
and more effective
high-dose
affected.
4-6 Km-Mfx-Pto-Cfz-Z-H
regimens.
An estimated 480 000 people
developed MDR-TB

THE SHORTER
MDR-TB REGIMEN
REGIMENCOMPOSITION
4-6 Km-Mfx-Pto-Cfz-Z-H

-E / 5 Mfx-Cfz-Z-E

Km=Kanamycin; Mfx=Moxifloxacin;
Km=Kanamycin; Mfx=M
Pto=Prothionamide; Cfz
Pto=Prothionamide; Cfz=Clofazimine;
Z=Pyrazinamide; Hhigh-do
Z=Pyrazinamide; H
=high-dose Isoniazid;
E=Ethambutol

in 2014 and 190 000 people died as a result of it.

MDR-TB cannot be treated with the standard 6For
more information
month course of first-line
medication
which is please visit: www.who.int/tb
effective in most TB patients. Patients with
World Health Organization May2016
rifampicin-resistant or MDR-TB are treated with
a
high-dose
different combination of second-line drugs,

Shorter MDR-TB regimen (2)

Treatment success versus failure/relapse/death
Resistance pattern
All cases regardless of
pyrazinamide and
fluoroquinolone
susceptibility
Pyrazinamide resistant;
fluoroquinolone resistant
Pyrazinamide resistant;
fluoroquinolone susceptible
Pyrazinamide susceptible;
fluoroquinolone resistant
Pyrazinamide susceptible;
fluoroquinolone susceptible

Shorter MDR-TB regimen

Conventional MDR-TB
regimen

% (95% CI)

% (95% CI)

1008/1116

90.3% (87.8%
92.4%)

4033/5850

78.3% (71.2%
84%)

19/28

67.9% (47.6%
84.1%)

81/137

59.1% (50.6%
67.1%)

90/100

88.8% (47.3%
98.6%)

840/1075

81.4% (71.6%
88.4%)

12/15

80.0% (50.0%
94.1%)

72/120

64.4% (49.6%
76.9%)

121/125

96.8% (77.3%
99.6%)

890/1119

83.5% (75.7%
89.2%)

Conclusions
1. MDR/XDR-TB is a global threat and a world challenge
2. The Current Situation is of serious concern and probably getting worse
3. With adequate clinical and operational management, all TB cases have a
chance to be cured, even those with very extensive pattern of resistance
4. The first priority to fight against MDR/XDR-TB is to strengthen the NTP with
good management of susceptible TB cases
5. However, to think to a favourable Future it is necessary to increase notably
the rate of detection (until 90%) and cure (until 90%) of these MDR/XDR-TB
cases