Transcript Slides - View the full AIDS 2016 programme

Innovations in TB treatment :
what the future holds
C. Padmapriyadarsini
National Institute for Research in Tuberculosis
Indian Council of Medical Research, Chennai, India
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1.2 million Incident TB cases in PLHIV
Proportion of TB cases co-infected with HIV
was highest in countries in African region
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HIV And TB : Partners in Crime
• WHO Global Report 2015,
– Percentage of TB patients with known HIV status highest in
African region (79%)
– Number of notified HIV+TB patients on ART has grown from 2004
– HIV ass. TB deaths accounted for 25% of all TB deaths
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Current Treatment Guidelines for TB
• Drug Susceptible TB : 6-months regimen 2EHRZ/4RH, cure
rate >90%
• Multi-drug resistant TB: At least 20 – 28 months regimen
with IP of at least 8 months with minimum 4 II-line drugs
/PYZ/and an injectable
• Extensively drug-resistant TB : longer to treat than MDR-TB
and requires the use of third-line anti-TB drugs
• Shortening Duration of Treatment for DS & DR-TB
– ReMOX, Oflotub, Rifaquin trials
• Newer Regimens for DS & DR-TB : Bangladesh regimen / STREAM
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Promising TB Drug pipeline
Combining these new drugs with existing TB drugs offers hopes for
regimens – better tolerated, shorter duration with few drug-interactions
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4-month thrice-weekly regimens of
Gatifloxacin or Moxifloxacin with HRZ, were
inferior to standard 6-month regimens
Regimen
Pts
2 month sp.
Culture Neg
2 GHRZ3
2 GHR3
136
83%
95%
16%
2 MHRZ3
2 MHR3
2 EHRZ3
4 HR3
115
88%
98%
10%
165
78%
97%
6%
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Favorable Relapse
response
Jawahar et al.PLoS ONE 2013; 8(7): e67030
Shortening course of treatment : DS-TB
Oflotub study
4-mon Gatifloxacin regimen
Regimen
Fav.
Relaps
Outcom
2 GHRZ /
2 GHR
(917)
79%
15%
2 EHRZ /
4 HR (919)
83%
7%
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ReMOX study
4-mon Moxifloxacin regimen
High Dose Rifapentine & Moxifloxacin
• 2EHRZ/4RH vs 2MEHRZ/4MRif1 (1200mg) vs 2EMRZ/2MRif2 (900mg)
• 6-monthly regimen of weekly high-dose rifapentine & Moxifloxacin was as
effective as control regimen
• It was also safe, well tolerated, reduced number of tablets needed in a course of
Rx from 360 to 140, reduced frequency of tablets from every day to once a week.
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N Eng J Med 2014; 372(17)
Intensive Continuation
phase
phase
3 RHZEM
2 RHZEM 2 RHM
2 RHZEM 2 RHM3
2 RHZEM
2 RHZE 3
2 RHEM3
4 RH3
% Pts with neg cultures
Moxifloxacin containing 5-drug regimen showed
higher sputum culture conversion in first 2months than thrice weekly 4-drug regimen
95
100
90
80
70
60
50
40
30
20
10
0
Control
Moxifloxacin
84
81
49
60
27
14
8
0
15
30
45
Days of Treatment
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Velayudham et al. Clin Infect Dis 2014;59(10):e142
60
Shorter Standardized
Regimen for MDR-TB
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AJRCCM 2010;182(5):684-92.
STREAM Trial – Stage I
• Determine whether a 9-month treatment regimen, that
showed cure rates exceeding 80% during a pilot programme
in Bangladesh, could achieve similar success in other
settings, with successful outcome being as good as that in
longer control regimen (G-M)
• 421 participants / Recruitment complete / Results in early 2018
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ISRCTN78372190
Data from
Bedaquiline
containing
regimens
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Infect Drug Resist. 2015;8:367-78
STREAM Trail – Stage II
• Comparison of a 6 and 9 month bedaquilinecontaining regimen against the WHO and Bangladesh
regimen
– Reg 1: Completely oral/Injectable replaced with Bdq
– Reg 2: 6-month regimen, with BDQ
Injectable given for only 2 months
– Reg 3 : 9-month regimen
– Reg 4: WHO Control regimen
• Enroll 1155 patients
• Results of Stage 2 are expected in 2021
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NCT02409290
Oral regimens : 1. NEXT Trial
• Phase 3, Prospective Open label RCT to evaluate a 6-9
month injection free regimen containing bedaquiline,
linezolid, levofloxacin, ethionamide/high dose isoniazid,
and pyrazinamide for Patients With MDR-TB
• Outcome : Treatment success, defined as the sum of
cured or treatment completed cases, 24 months after
initiation of treatment
• To enroll 300 pts – currently enrolling in S.Africa Expected completion Jan 2019
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NCT02454205
2. Nix-TB Trial (BPaL)
• All-oral regimen for XDR-TB
– To assess Safety, Efficacy, tolerability & PK of 6 months of
Bedaquiline + PA-824 (200mg od) + Linezolid (600mg bd)
in patients with pulmonary XDR-TB or treatment non
responsive MDR TB
– Recruiting 14 years & older at three sites in South Africa
• Incidence of bacteriologic failure or relapse or clinical failure
through follow up until 24 months after the end of
treatment
• Enrolling - 200 participants - Expected completion 2018
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NCT02333799
3. NC-005 trial (BPaZ)
• 2-week study found that Bedaquiline , PA-824 and
Pyrazinamide (BPaZ) regimen killed more than 99% of
TB bacteria over course of 14 days
• Determine the efficacy, safety and tolerability of
combinations of Bedaquiline, Moxifloxacin, PA-824
and Pyrazinamide regimens during 8 weeks of
treatment in adults with Newly Diagnosed DS or
MDR-TB
• Plan in 10 sites across Uganda, S.Africa & Tanzania
• 240 participants. Expected completion 2018
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NCT02193776
STAND TRIAL (PaMZ)
• Phase 3 Open-Label Partially Randomized Trial
• To assess the efficacy, safety and tolerability of a
combination of moxifloxacin, PA-824, and pyrazinamide
treatments
– After 4 & 6 months of treatment in adults with DS-PTB
– After 6 months of treatment in adults with smear
positive pulmonary MDR-TB
• Outcome : Incidence of combined bacteriologic failure or
relapse of clinical failure at 12 months from start of Rx
• To enroll 1500 pts
• Started Feb 2015; Expected completion May 2018
• Currently suspended participant recruitment
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NCT02342886
Delamanid for MDR-TB
• Phase 3, Multicenter, Randomized, Double-blind,
Placebo-controlled, Parallel Group Trial
• Evaluate the Safety & Efficacy of Delamanid 200 mg
once daily x 6 months in pulmonary MDR TB
• Outcome: Time to Sputum Culture Conversion ,
Mortality, Rx success & Failure
• Ongoing - Estonia, Latvia, Lithuania, Moldova, Peru,
South Africa
• 511 pts. Exp completion May 2017
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NCT01424670
Other DR-TB Clinical Trials
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Trials for Pediatric Drug Resistant TB
Trial
Population
Outcome
PK, Safety,
Tolerability and
Anti-mycobac
activity of BDQ
with OBR
60 HIV uninfected
children & adolescents
<18 Years with
Confirmed or Probable
Pulmonary MDR-TB
No. of
Adverse
events
Max. & Min
Plasma conc
Time to
Max. Plasma
conc
4-Age based cohorts :
12-17; 5-11, 2-5, <2 yrs
Safety, Efficacy,
Tolerability, PK
of 6-mon Rx
with OBR +
Delamanid
DLM BD x 6
months
36 Pediatric MDR TB
4-Age based cohorts :
12-17; 5-11, 2-5, <2 yrs
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Enrollment Exp. End
stats /site
South
Dec
Africa
2022
(Recruiting)
Philippines
Russia
India
Safety,
Recruiting
Tolerability,
Plasma conc Philippines
South
Africa
NCT02354014 & NCT01859923
August
2019
First case of XDR-TB treated with
both Delamanid and Bedaquiline
• 39 yrs female / Indian / 65-kg / 4- retreatment
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ERJ Express June 2016
Host directed therapies for TB Rx
• An effective host immune system is crucial for the
eradication of M. tb infection
• To reduce destructive inflammatory responses
– pro-inflammatory and anti-inflammatory
eicosanoids (imatinib)
– Repurposing drugs : efflux pump inhibitors
– Immunotherapy
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To improve efficiency of new drug
evaluation
• New Regimens & 14-day
EBA studies
• New design for Phase II &
III trials (MAMS)
• Biomarkers for
monitoring TB treatment
response, cure & relapse
• Growing networks for
drug development and
evaluation
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Conclusions
• Despite the introduction of cheap and effective
treatment, TB is still found in every corner of
the globe
• Is threatening the gains made in TB control
• Great need for shorter, less toxic treatment
regimens, new drugs as well as better and
shorter ways of evaluating new TB drugs and
drug regimens
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Perspectives
• Recent years, there has been some investment
into new TB drug development and evaluation
• Urgent need for increased coordination and
enhanced collaboration among drug developers,
funding agencies & clinical trial networks to bring
more new & safe drugs / regimens easily
accessible to patients faster and sooner
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