The Threat and the Challenge of MDR-TB.

A Curable Disease with a Proper Clinical and Operational Management
43rd Union World Conference Malaysia, November 14, 2012

Prof. José A. Caminero Luna
Department of Pneumonology University Hospital of Gran Canaria “Dr. Negrín” Las Palmas de G.C. SPAIN (The Union)

Tuberculosis is certainly the disease that has provoked the most damage (diseases and deaths) to mankind throughout history. It has caused death and disease for perhaps more than 3 million years and, as a rule, has affected the poorest strata of society
J.A. Caminero. Eur Respir J 2004, 25: 895

Amenophis IV and

Nefertiti
(Deceased TB)

1360 b. c.

Simón Bolívar (1783-1830)
Liberator of the Americas. Died of TB after a long illness

Mycobacterium tuberculosis
It is probably the infectious agent that has caused the greatest number of Deaths in the History of Humanity

Today it is still considered as the 2nd Greatest Murderer, out of all single Pathogens

Fate of TB patients Without Treatment. India 1961-68
60

%

50 40 30 20 10 0

* *
*

Cured

Positives

Dead
TB Smear + TB Smear -

* Grzybowski S, Enarson DA Bull Int Union Tuberc Lung Dis 1978;53(2):70-5.

Two Genius of the Medicine: Waskman and Fleming

Dr. Selman A. Waksman
- Discovered STREPTOMYCIN in 1943 - Together with his laboratory assistant A. Schatz

Ma Z, Lienhard C. Clin Chest Med 30 (2009) 755–768

INH-PAS-SM

ANTIMYCOBACTERIAL DRUGS
1. ISONIAZID 3. PYRAZINAMIDE 5. STREPTOMYCIN 7. KANAMYCIN 9. ETHION. – PROTHIONAMIDE 11. P.A.S. 13. QUINOLONES:
- OFLOXACIN - LEVOFLOX. - GATIFLOXACIN - MOXIFLOX

2. RIFAMPICIN 4. ETHAMBUTOL 6. CAPREOMYCINE 8. AMIKACIN 10. CYCLOSERINE-TERIZ. 12. THIACETAZONE 14. CLOFAZIMIDE 15. Others:
- MACROLIDES, CLAVULANATE.,

Etc

AT LEAST 4 FOR GOOD RETREATMENT!

The Threat and the Fear of MDR/XDR- TB

TB  An INCURABLE disease ?

The Threat of MDR-TB?
“It may affect over 10 million people world-wide…” JAMA (2000) “MDR Tuberculosis … A global pandemic” BMJ (1998) “More fatal than AIDS” Washington Post (1998) “MDR … a time bomb” Am Rev Respir Dis (1985) “It may destabilise Russian society” NDCF (2000) “Once liberated, it will be impossible to control...” WHO publicity (1997)

Consequences of MDR/XDR-TB
 Poor response to standardised treatment  Long duration of contagiousness

 High risk of morbidity and mortality
 Individualised treatment more costly
Difficult management --> requires specialized Training

The global TB situation, 2011
Estimated number of cases, 2011 Estimated number of deaths, 2011

All forms of TB HIV-associated TB Multidrug-resistant TB

8.7 million
(8.3–9.0 million)

990,000*
(840,000–1.1 million)

1.1 million
(1.0–1.2 million)

430,000
(400,000–460,000)

630,000
(460,000–790,000)

[of 12m prevalent cases]
* Excluding deaths attributed to HIV/TB

Source: WHO Global Tuberculosis Report 2012

% of MDR among new TB cases (1994-2011 data)

Global average 3.7% (2.1 – 5.2%)
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.  WHO 2012. All rights reserved

% of MDR among previously treated TB cases (1994-2011 data)

Global average 20% (13 – 26%)
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.  WHO 2012. All rights reserved

- Between November 2009 and December 2010, 156 consecutively diagnosed new and 68 previously treated TB - MDR-TB was found in 35.3% (95% CI 27.7–42.8) of new patients and 76.5% (95% CI 66.1–86.8) of those previously treated. - Overall, nearly one in two patients enrolled had MDR-TB.

- Extensively drug-resistant TB was reported in 15 of the 107 MDR-TB patients (14.0%, 95% CI 7.3–20.7).

High prevalence of childhood multi-drug resistant tuberculosis in Johannesburg, South Africa: a cross sectional study
Lee Fairlie,Natalie C Beylis, Gary Reubenson, David P Moore,and Shabir A Madhi

BMC Infect Dis. 2011; 11: 28.

-1317 children were treated for TB in 2008

- DST was performed in 148 (72.5%) of the 204 children who had culture-confirmed tuberculosis.
- The prevalence of isoniazid-resistance was 14.2% (n = 21) and the prevalence of MDR-TB 8.8% (n = 13) (95%CI, 4.8-14.6%). - The prevalence of HIV co-infection was 52.1% in children with drug susceptible-TB and 53.9% in children with MDR-TB. - Ten (76.9%) of the 13 children with MDR-TB received appropriate treatment and four (30.8%) died at a median of 2.8 months (range 0.1-4.0 months) after the date of tuberculosis investigation.

Countries (84) reporting ≥1 XDR-TB case by Oct 2012

The Threat and the Fear of MDR/XDR- TB

TB  An INCURABLE disease ?

The Resistant M. tuberculosis

day by day is more
RESISTANT

M tuberculosis vs Human Specie
The Millennial Fight between 2 Species

Mono - Resistance
Dr. Selman A. Waksman
- Discovered STREPTOMYCIN in 1943 - Together with his laboratory assistant A. Schatz

Poly - Resistance
INH-PAS-SM

M. TB Resistant to 2 or more Drugs

Multi–Drug-Resistance RIFAMPICINA (MDR)

Discovered in 1963 by Lepetit Laboratories

M. TB Resistant to, at least, H+R

Extensively–Drug-Resistance (XDR)
CONCLUSSIONS:

1. Only ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin and moxifloxacin have been tested in randomized controlled trials for treating tuberculosis. 2. We cannot recommend ciprofloxacin in treating tuberculosis. 3. Trials of newer fluoroquinolones for treating tuberculosis are needed and are on-going. 4. No difference has been demonstrated between sparfloxacin and ofloxacin in drug-resistant tuberculosis.

MDR-TB plus Resistance to FQ and 1 SLDI (Kn, Ak, Cm)

Already there are TB Cases with Resistance to all these Drugs

Totally-Drug Resistant (TDR-TB)?

Ma Z, Lienhard C. Clin Chest Med 30 (2009) 755–768

Totally Drug Resistant (T.D.R. – TB)
- In 2007, two patients with strains having resistance to all first and second-line anti-TB drugs which were tested were reported from Italy (1) - In 2009, 15 TB patients in Iran were reported to be resistant to all anti-TB drugs tested (2)

- In December 2011, clinicians in Mumbai, India, described four patients with “TDR-TB” (3). A few weeks later, the Times of India reported another eight cases in Mumbai.
1) Migliori GB, et al. Euro Surveill. 2007 May;12(5):E070517.1 2) Velayati AA, et al. Chest. 2009 Aug;136(2):420–5. 3) Udwadia ZF, et al. Clin. Infect. Dis. 2012 Feb 15;54(4):579–81.

The Battle between the Human Species and M. tuberculosis

1. 2. 3. 4. 5.

Mono-Resistance Poly-Resistance M.D.R. X.D.R. T.D.R. (Totally Resistant TB)

Is DR –TB an Incurable Epidemic ?
Not always!! With adequate Management it is curable, although the possibility of success can decrease notably

Ma Z, et al. Lancet 2010; 375: 2100–09

Patients with an Extensive pattern of Resistance has always existed , but with an Adequate Clinical Management and Enough Resources a good Rate of Success is Possible

Possibilities to Cure MDR/XDR-TB
Available Evidence

1. Historic Evidence (Pre-Rifamp. period)

2. Current Evidence
1. MDR-TB Patients (2 Meta-analysis) 2. XDR-TB Patients (1 Systematic Rev. and 1 Meta-analysis)

The MDR/XDR-TB patients of 1950-70s were those with Resistance to H+S+PAS (then there was not Rif nor Fq)

Pre-RIF and Pre-Fq Era
Patients with Resistance to INH+SM treated with only 3 Drugs
Caminero JA. Int J Tuberc Lung Dis 2006, 10: 829-837

Reference
USA. Schwartz
JAMA 1962; 181:134

Drugs
Kn-Z-Eth-Cs

Follow-up (m) 6-12

Nº Cases
64

Sm Conversion

57 %
100 %

UK. Pines
Chest 1962; 53: 163

Z-Eth-Cs-Vi-Th

12-24

39

Morocco. Chicou
RevTuberc1962;26:867

Kn-Eth-Cs-Vi-P

4-12

31

67,7 %
94,8 %

USA. Kass
Tubercle1965;46:151-80

Kn-Z-Eth-Cs E-Cm-Th Eth-Cs-P

21-37

98

Germany. Schütz
PraxisPneum1964;18:288

6

34

85 %

Pre-RIF and Pre-Fq Era
Patients with Resistance to INH+SM treated with only 3 Drugs
Caminero JA. Int J Tuberc Lung Dis 2006, 10: 829-837

Reference
Hungary. Böszörmenyi
Tubercle 1965;46:143

Drugs
Z-Eth-Cs Kn-Z-Eth-Cs-

Follow-up (m) 3 6-60

Nº Cases
31 146

Sm Conversion

51,6 %
83.5 % 92,4 % 96 %

USA. Lester
AmRevRespirDis1968;97:392-8

Poland. Zierski
Tubercle 1964;45:96

Z-Eth-Cs

3-9

65

Czechosl. Tousek
Tubercle 1967;48:27

Z-Eth-Cs

60-84

55

Spain. March
RevClinEsp1968;109:117

Z-Eth-Cs-Vi-E

6-18

33

93,4 %

Possibilities to Cure MDR/XDR-TB
Available Evidence

1. Historic Evidence (Pre-Rifamp. period)

2. Current Evidence
1. MDR-TB Patients (2 Meta-analysis) 2. XDR-TB Patients (1 Systematic Rev. and 1 Meta-analysis)

September 2009

- Systematic search (to December 2008)  36 met inclusion criteria, representing 31 treatment programmes from 21 Countries
62% [95% CI 57–67] successful outcomes 13% [9–17] defaulted 11% [9–13] died 2% [1–4] were transferred out

- 34 clinical reports (mean 250 patients) met the inclusion criteria. - The proportion of patients treated successfully improved when: - Treatment duration was at least 18 months - Patients received DOT throughout treatment - Studies that combined both factors had significantly higher pooled success proportions (69%) than other studies of treatment outcomes (58%) - Individualized treatment regimens had higher treatment success (64%) than standardized regimens (54%), although the difference was not significant - Treatment approaches and study methodologies were heterogeneous across studies. - Many important variables, including patients’ HIV status, were inconsistently reported between studies.

MDR-TB Treatment in Children
- Systematic review and meta-analysis reviewed treatment outcomes for children with MDR-TB. - Eight studies, which reported outcomes on 315 patients, contributed to the database. - Average duration of treatment ranged from 6 months to 34 ms. - The pooled estimate for treatment success (defined as a composite of cure and completion) was 81.7% with death in 5.9%, and default in 6.2% of patients. - Adverse reactions occurred in 39.1% of the children, the most common of which were nausea and vomiting followed by hearing loss, psychiatric effects and hypothyroidism.
Ettehad D, Schaaf HS, Seddon JA, Cooke GS, Ford N. Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2012;12:449-56.

- Longer treatment duration and delayed sputum smear conversion were reported in most studies among XDR-TB patients. - Median time to sputum Smear conversion ranged 41– 56 days in MDR-TB patients, while it ranged 88–110 days in XDR-TB cases. - The median time to Culture conversion ranged 58–99 days in MDR-TB cases; it was substantially different in XDR-TB patients, ranging 60–195 days.

Sotgiu G. Eur Respir J 2009; 33: 871-881

- Very different Outcomes

- 13 observational studies covering 560 patients: - 43.7% (95% CI, 32.8%–54.5%) favorable outcomes - 20.8% (95% CI, 14.2%–27.3%) Died. - Studies in which a higher proportion of patients received a later-generation fluoroquinolone reported a higher proportion of favorable treatment outcomes (p= .012)

With each 10% increase in the proportion of patients receiving a latergeneration fluoroquinolone, there was a 4% increase in the proportion of patients with favorable outcomes.

Jacobson et al. CID 2010; 51 (July)

Patients with an Extensive pattern of Resistance has always existed, but with Adequate Clinical Management and Enough Resources a good Rate of Success is Possible

The Clinical Management of MDR or XDR-TB Patients is Key

MDR/XDR-TB Clinical Management
Many Controversial Issues to Address
- There are no Clinical Trials comparing different Regimen and Drugs - There are only personal experiences and publications showing very different results - The most important Recommendations/ Guidelines have changed in the last decades and are not in agreement - Currently there are very controversial issues, sometimes with no agreement
Caminero JA. Int J Tuberc Lung Dis 2006, 10: 829-837

MDR/XDR-TB Clinical Management. Controversial Issues
Caminero JA. Int J Tuberc Lung Dis 2006, 10: 829-837

1. How to approach Diagnosis of MDR? Reliability of DST

2. How Many Drugs to Treat MDR-TB ?
3. Rational Use of the FLD and SLD 4. Length of the Injectable (Intensive phase) 5. Role of Surgery in MDR-TB Treatment 6. Approach to the Ideal Regime in MDR-TB Standardized vs Individualized Regimes

M. tuberculosis Resistance

In TB, drug resistance is always the result of poor case management of drug sensitive tuberculosis cases

The first priority to fight against MDR/XDT-TB is to strengthen the NTP with a good management of

the susceptible TB

- 37 studies were included. Inappropriate treatment regimens were prescribed in 67% of studies. - The percentage of patients receiving inappropriate regimens varied between 0.4% and 100%. - In 19 studies the quality of treatment regimen reporting was low

Even for countries with unlimited resources, the time to generate a MDRTB case is less than the time required to cure it

PRIORITIES in a National Tuberculosis Programme (NTP)

1. To Avoid MDR-TB

4. To Avoid XDR-TB

PRIORITIES in a National Tuberculosis Programme (NTP)

1. To Avoid MDR-TB

4. To Avoid XDR-TB

THE BEST WAY TO AVOID MDR-TB (1)
To Give the best initial treatment when the patient presents TB for the first time.

2 HRZE / 4 HR
- Advisable Daily, at least in the Intensive Phase, but preferable along all the treatment

- EMB (or Intensive Phase) along all the treatment if Smear + at the end of the 2º month, or until knowing Susceptibility H+R

THE BEST WAY TO AVOID MDR-TB (2)

Directly Observed Treatment is fundamental to prevent Resistance emergence

PRIORITIES in a National Tuberculosis Programme (NTP)

1. To Avoid MDR-TB

4. To Avoid XDR-TB

THE BEST WAY TO AVOID XDR-TB (1)

- Selection of the Best SLD Regimen according the Classification of the MDR-TB (New, never receiving previously
SLD and receiving previously SLD)

- To support in the selection of this Regimen is essential to know the possible Resistance to Fq+SLDI in MDR-TB
- Surveillance to address the best SLD Regimen - Genotype SLD in all the MDR-TB patients previous to start the SLD Regimen

THE BEST WAY TO AVOID XDR-TB (2)

Directly Observed Treatment is fundamental to prevent Resistance emergence

Conclusions
1. MDR/XDR-TB is a global threat and a world challenge

2. With adequate clinical and operational management, all the TB
cases has a chance to be cured, even those with very extensive

pattern of resistance
3. The first priority to fight against MDR/XDT-TB is to strengthen

the NTP with a good management of the susceptible TB

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