Download EMERGING TREATMENT ISSUES IN MDR-TB

Treatment for
Multi-drug Resistant TB
STREAM Clinical Trial
[INSERT NAME OF PRESENTER]
2
Status of MDR-TB world-wide
Burden of disease
• In 2015, of the estimated 580,000 people eligible for
MDR-TB treatment, only 125 000 (~ 1 in 5) were
started on treatment
• Outcomes of MDR/RR-TB patients in the 2013 cohort:
▫
▫
▫
▫
▫
52% were successfully treated
17% died
15% were lost to follow-up
9% were determined to be treatment failure
7% had no outcome information
3
Outcomes of MDR TB treatment
Source: Global Tuberculosis Report 2016
4
Where does MDR TB occur?
5
Treatment of drug sensitive TB
• Two main drugs for treatment of DS TB
▫ Isoniazid
▫ Rifampicin
• Treatment taken 6 months by mouth
• Treatment very successful
▫ >90% cure for patients who take their medication
• If resistance to rifampicin occurs treatment
▫ takes much longer
▫ more side effects does not work as well
6
How does resistance to TB medicines
happen?
• Acquired resistance happens when
▫ Patients with drug sensitive TB can’t or don’t take
medications as required
 Miss doses or not given the correct doses to take
 Pharmacy runs out of medicines
 Get side effects and stop treatment
• Transmitted resistance happens when
▫ Patients get infected with resistant TB
 TB organism that infects the patient is resistant to
medication from the start of treatment
7
What if TB resistance exists?
• Rifampicin is the best currently available TB
medicine
• If resistance to Rifampicin exists, more
medications have to be given:
▫ not as strong
▫ worse side effects
• Patients have to have injections for 6 months
• Treatment less effective
▫ Only ~50% of patients are cured
8
Definitions of TB Drug Resistance
Drug
Sensitive
Multi-drug
resistant
Pre-XDR
Rifampicin
Rifampicin
Rifampicin
Rifampicin
Isoniazid
Isoniazid
Isoniazid
Isoniazid
Fluoroquinolne
Fluoroquinolne
Extensively
drug resistant
or
Amikacin or
kanamycin or
capreomycin
Amikacin or
kanamycin or
capreomycin
9
How is DR TB treated?
Introdion
Objectif
Méthodes
Conclusion
10
Conventional/longer regimens for MDR-TB
• Usually between 20-24 months, with 2 phases
• Intensive phase
▫
▫
▫
▫
▫
▫
Quinolone (moxifloxacin)
Injectable agent (amikacin, kanamycin or capreomycin)
PZA
Ethionamide
Terizidone/cycloserine
Ethambutol (depends on local prevalence or resistance)
▫
▫
▫
▫
▫
Injectable agent (amikacin, kanamycin or capreomycin)
PZA
Ethionamide
Terizidone/cycloserine
Ethambutol (depends on local prevalence or resistance)
• Continuation phase
11
New WHO recommendation for shorter
regimens - 2016
▫
For most patients
with MDR-TB, a
shorter regimen
(9-12 months) can
be used instead of
a longer,
conventional
regimen
▫
But: WHO’s recommendation acknowledges that
additional evidence is required
12
Emerging evidence for new regimens
• Results for six groups of patients with MDR-TB
in Bangladesh who received a shortened regimen
indicated there might be better treatment
options for MDR-TB, even without new drugs
▫ Van Deun A, Maug AKJ, Salim MAH, Das PK, Sarker MR, Daru
P, et al. Short, Highly Effective, and Inexpensive Standardized
Treatment of Multidrug-resistant Tuberculosis. Am J Respir Crit
Care Med. 2010; 182(5): 684-92.
13
Results of 9-month regimen–Bangladesh
Published cohort (206 pts)
Cure
Cohort update (515 pts)
82.5%
81.2%
Completion
5.3%
3.3%
Default
5.8%
7.8%
Death
5.3%
5.6%
Failure
0.5%
1.4%
Relapse
0.5%
0.8%
Overall success rate:
Overall success rate:
87.9% (95% CI 82.7, 92.6)
84.5% (95% CI 0.81, 0.88)
Introdion
Objectif
Conclusion
Méthodes
Am J Respir Crit Care Med Vol 182. 684–692, 2010
Aung et all, IJTLD 18(10):1180–1187, 2014
Bangladesh regimen–Intensive Phase
• Quinolone (moxifloxacin/
gatifloxacin)
• Injectable agent (Amikacin,
kanamycin or capreomycin)
• PZA
• Ethionamide/prothionamide
• High dose INH
• Clofazamine
• Ethambutol
15
Bangladesh regimen–Continuation Phase
•
•
•
•
•
Quinolone (moxifloxacin/gatifloxacin)
PZA
Clofazamine
Ethambutol
No injectable agent
16
Conclusions
• Drug resistant TB affects > half a million people
worldwide
• Only half of those who are treated for Drug resistant TB
are successfully treated
• Until recently, treatment for Drug Resistant TB was
based on very low quality evidence
• Promising new treatment regimens for MDR-TB are
emerging:
▫
▫
▫
▫
Better treatment outcomes
Shorter
Still includes injectable agents
Do not yet incorporate new drugs
• However, there continues to be an urgent need for
research
The STREAM Trial
[INSERT NAME OF PRESENTER]
18
Building evidence for better MDR-TB
regimens
Cohort studies
Randomized trials
•
•
•
•
•
•
• STREAM
Cameroon
Benin
Niger
Swaziland
Other African countries
Uzbekistan
19
STREAM objectives
vs.
Conventional
regimen
(20-24
months)
vs.
Shorter
regimen
(6 months)
Bangladesh
regimen w/
Moxi
(9 months)
vs.
All oral
regimen
(9 months)
20
STREAM Stage 1
• Control regimen (A) 
STREAM Stage 1 sites
locally used WHOrecommended regimen
• Study regimen (B) 
similar to Bangladesh
shorter regimen but
high-dose moxifloxacin
replaces high-dose
gatifloxacin
Sites: Ethiopia (2), South Africa (3), Vietnam
and Mongolia (1)
21
The study regimen (B) – 9 months
Weeks
Drug
Kanamycin*
Isoniazid (H)
Prothionamide
Clofazimine
Moxifloxacin
Ethambutol
Pyrazinamide
2000 mg
Drug doses by weight group
< 33 kg
1 - 16
1 - 16
1 - 16
1 - 40
1 - 40
1 - 40
1 - 40
33 - 50 kg
> 50 kg
15 mg per kilogramme body weight
300 mg
400 mg
600 mg
250 mg
500 mg
750 mg
50 mg
100 mg
100 mg
400 mg
600 mg
800 mg
800 mg
800 mg
1200 mg
1000 mg
1500 mg
• Kanamycin 3 times/week after week 12
The intensive phase may be extended by 4 or 8 weeks if smear conversion
has not occurred by 16 or 20 weeks
22
STREAM Stage 1 study population
• Adults who have given consent
• Smear-positive pulmonary tuberculosis or, if
HIV positive, may be smear negative
• Resistance to rifampicin
• No resistance to fluoroquinolone or 2nd-line
injectables
• No pre-existing QT prolongation >500msec
• If pre-menopausal woman, not pregnant or
breast feeding and agrees to use effective barrier
contraception/IUCD during treatment
23
STREAM Stage 1 status
• Enrolment started July 2012
• 424 patients enrolled
▫ Target reached and exceeded
• Intake closed June 30th 2015
• Retention rates are high
• Last patient visit expected Q4 2017
• Results from Stage 1 expected Q1/2 2018
24
STREAM Stage 2
vs.
Conventional
regimen
(20-24
months)
vs.
Shorter
regimen
(6 months)
Bangladesh
regimen w/
Moxi
(9 months)
vs.
All oral
regimen
(9 months)
25
STREAM Stage 2 history
• After provisional licensing of first new TB drug
for ~50 years (bedaquiline) in 2013, STREAM
trial sponsor asked:
▫ Is it possible to add regimens to the STREAM trial?
▫ What would be the appropriate regimen(s) to add?
• After extensive discussions with experts it was
agreed that the primary interest to patients and
programmes would be:
▫ A fully oral regimen (no kanamycin) and/or
▫ A shorter/simpler regimen
26
STREAM Stage 2 regimens
STREAM Stage 2 patients take one of four
regimens:
A: the locally used WHO approved MDR-TB
regimen
B: the modified 9-month Bangladesh regimen
studied in Stage 1
C: a fully oral 9-month regimen
D: a six-month regimen
Both regimens C and D will contain bedaquiline
throughout.
27
STREAM Stage 2 regimens
28
STREAM Stage 2 objectives
• Assess whether Regimen
C, the fully oral
regimen, is as effective as
Regimen B at 76 weeks (18
months)
• Assess whether Regimen
D, the 6-month
regimen, is as effective as
Regimen B at 76 weeks (18
months)
29
STREAM Stage 2 status
• Enrolment began in
March 2016
STREAM Stage 2 sites
▫ >70 patients enrolled
• Currently enrolling
patients in Ethiopia,
Mongolia, South
Africa and Moldova
• Trial planned for 9
countries and 15+ sites
Current sites: Ethiopia (2), South Africa (3),
Mongolia (1), Moldova (1)
30
STREAM Stage 2 study population
• The same criteria as Stage 2 with
▫ Additional safety criteria for liver, kidney,
pancreatic and electrolytes function
▫ Increased focus on excluding risk factors for
cardiac arrhythmias
▫ A chest X-ray compatible with a diagnosis of
pulmonary TB
▫ HIV infected participants must CD4 count more
than 50 cells/mm3
31
STREAM Stage 2 timeline
• Plan to complete enrolment in less than 3
years
• Last patient enrolled Q4 of 2018
• Last patient reaches 18 months postrandomisation Q2 of 2020
• Last patient completes long term follow-up
Q2 of 2021
32
STREAM Partners
Funder: USAID
Funder:
Janssen
Pharmaceuticals
(Stage 2 only)
Sponsor:
Microbiology:
Institute of
Tropical Medicine,
Antwerp
Design, Management, Analysis
Trial sites
Impact Assessment:
Liverpool School
of Tropical
Medicine
33
Conclusions
• Drug resistant TB affects > half a million people
worldwide
• Only half of those who are treated for drug resistant TB
are successfully treated
• Until recently, treatment for drug resistant TB was based
on very low quality evidence
• Promising new treatment regimens for MDR-TB are
emerging:
▫
▫
▫
▫
Better treatment outcomes
Shorter
Still includes injectable agents
Do not yet incorporate new drugs
• However, there continues to be an urgent need for
research
34
Conclusions
• STREAM aims to improve the evidence base for
better MDR-TB treatment regimens
▫ Shorter regimens (Stage 1 and 2)
▫ All-oral regimen (Stage 2)
▫ New drugs (Stage 2)
• STREAM uses a randomized control trial design
to strengthen quality of evidence
• Results from Stage 1 expected shortly
• Stage 2 still scaling up
▫ Results not expected until after 2021
Thank you