Download Dr F Conradie- The Bedaquiline Journay

The Bedaquiline Journey
Dr Francesca Conradie
Treatment of Drug sensitive TB
6 months of treatment consisting of
– Intensive phase- INH, Rif, PZA and
Ethambutol for 2 months
– Continuation phase- INH and Rif
– Medications are co-formulated
– Do not interact with standard first line
antiretrovirals
– Can be used in pregnancy
– Basis of DOTS
TB resistance
DS
MDR
Pre-XDR
XDR
Rifampicin
Rifampicin
Rifampicin
Rifampicin
Isoniazid
Isoniazid
Isoniazid
Isoniazid
Fluoroquinolne
Fluoroquinolne
or
Amikacin or
kanamycin or
capreomycin
Amikacin or
kanamycin or
capreomycin
TB resistance
DS
MDR
Pre-XDR
XDR
Rifampicin
Rifampicin
Rifampicin
Rifampicin
Isoniazid
Isoniazid
Isoniazid
Isoniazid
Fluoroquinolne
Fluoroquinolne
or
Diagnosed by
GXP
Amikacin or
kanamycin or
capreomycin
Amikacin or
kanamycin or
capreomycin
TB resistance
DS
MDR
Pre-XDR
XDR
Rifampicin
Rifampicin
Rifampicin
Rifampicin
Isoniazid
Isoniazid
Isoniazid
Isoniazid
Fluoroquinolne
Fluoroquinolne
or
Amikacin or
kanamycin or
capreomycin
Diagnosed by LPA
and Culture
Amikacin or
kanamycin or
capreomycin
TB resistance
DS
MDR
Pre-XDR
XDR
Rifampicin
Rifampicin
Rifampicin
Rifampicin
Isoniazid
Isoniazid
Isoniazid
Isoniazid
Fluoroquinolne
Fluoroquinolne
or
Amikacin or
kanamycin or
capreomycin
Diagnosed by
Culture
Amikacin or
kanamycin or
capreomycin
MDR-TB Cases Started on Treatment
Extent of the problem in South Africa
3000
2007
2008
2009
2010
2011
2012
2500
2000
1500
1000
500
0
EC
FS
GP
KZN
LP
MP
NC
7
NW
WC
MDR-TB Treatment Outcomes
(24 months)
60
Rx Success rate
Defaulter rate
Death Rate
2007
2008
2009
Failure Rate
50
40
30
20
10
0
2010
XDR- TB Started on treatment
300
2007
2008
2009
2010
2011
2012
250
200
150
100
50
0
EC
FS
GP
KZN
LP
MP
NC
NW
WC
XDR-TB Treatment Outcomes
(24 months)
60
Rx Success
Defaulter rate
Death rate
Failure rate
50
40
30
20
10
0
2007
2008
2009
2010
Challenges in DR TB treatment
Toxic medications
Poor efficacy
Very long duration
Overlapping toxicities with ART
Poor evidence on treatment options
South Africa guidelines for the
management of Drug Resistant TB
The standardised regimen consists of at least six months intensive phase
treatment with five drugs:
- Kanamycin/amikacin,
- moxifloxacin,
- ethionamide,
- terizidone and
- pyrazinamide
These are taken at least six times per week
during the injectable phase followed
by a continuation phase treatment with four drugs
moxifloxacin, ethionamide, terizidone and pyrazinamide)
taken at least six times per week.
Levofloxacin is used in patients
who may not tolerate moxifloxacin
Current treatment regimens
Intensive Phase: Standardised Regimen for Adult and
Children 8 Years and Older
Current treatment regimens
Continuation Phase: Standardised Regimen for Adult
and Children 8 Years and Older
Current treatment for MDR TB
+/- ethambutol
Continuation phase- for at least 18 months following
culture conversion
Guidelines are based on expert opinion
Strong advice with weak/ no evidence
Poor evidence base for current regimen
In summary
Relatively
ineffective
Poor evidence
base for current
guidelines
Long duration
Significant and
debilitating side
effects
Relatively ineffective
Significant and debilitating side
effects
Short term and usually reversible
– Painful injections
– Nausea and vomiting
– Hepatitis
Medium term
– Kidney failure
– Psychiatric side effects (depression, paranoia)
– Peripheral neuropathy (tingling, numbness, pain)
Long term and usually irreversible
– Hearing loss due to the injectable drugs (~30% of
patients in some settings)
In order to detect
hearing loss which
occurs in up to 30% of
MDR TB patients, we
monitor their hearing
Audio Booth
Promising new drugs
New Drugs
– bedaquiline
– sutezolid
– PA-824
– Delaminid
Re-purposed:
– Linezolid
– Clofazamine
Bedaquiline
BDQ is diarylquinoline compound with a new
mechanism of antituberculosis action by specifically
inhibiting mycobacterial ATP synthase
C208 Stage 2: randomised,
double-blind, multicentre study
Last study visit
120 weeks
(30 months)
18–24-month total MDR-TB treatment
Investigational
treatment phase
• 160 adults with
untreated smearpositive MDR-TB
• Randomised 1:1;
stratified for site and
lung cavitations
• Bedaquiline 400mg
qd for 14 days, then
200mg tiw
24 weeks
Placebo + BR
Post-investigational
treatment phase
96 weeks
BR only
120-week
analysis
24-week
evaluation
24 weeks
Bedaquiline + BR
≥6 months
treatment-free
follow up
96 weeks
BR only
Diacon AH, et al. N Engl J Med 2014;371:723–32
C208 Stage 2: primary and
secondary analysis
Primary analysis: time to sputum culture conversion (SCC) at
24 weeks of treatment
• SCC defined as two consecutive negative MGIT cultures
collected
≥25 days apart and not followed by a confirmed positive
culture
• Data for patients who discontinued treatment, died, or did not
have sputum-culture conversion before 24 weeks were
censored at the last assessment, regardless of the culture
status at the time of study dropout or death, and these
patients were considered to have had no response
– Secondary analysis: culture conversion rates at 24
weeks and 120 weeks
Diacon AH, et al. N Engl J Med 2014;371:723–32
Efficacy analysis (C208 Stage 2): significant reduction in
median time to culture conversion compared with placebo
Median time to culture conversion (mITT) = 83 days for bedaquiline versus 125 days for
placebo
Proportion of culture positive patients
1.0
Primary analysis:
p<0.001 for the
difference in TtC
0.8
Secondary analysis:
p=0.008 for the
difference in proportion
0.6
50%
0.4
Placebo + BR
(n=81)
58%
0.2
Bedaquiline + BR
(n=79)
79%
0
BAS
4
8
12
Time to culture conversion (week)
p-value from Cox proportional model adjusting for strata
The intersection of horizontal dotted line and each treatment arm
represents the median time to sputum conversion
16
20
24
Diacon AH, et al. N Engl J Med 2014;371:723–32
C208 Stage 2: efficacy
conclusions
Responder rates were greater after treatment with bedaquiline + BR in
comparison with placebo + BR
Addition of bedaquiline to a five-drug MDR-TB regimen
resulted in
– A significantly shorter time to culture conversion within
24 weeks compared with placebo
• median 83 days versus 125 days (p<0.001)
– A higher sputum conversion rate compared to placebo at
24 weeks (79% versus 58% [p=0.008]) and 120 weeks (62%
versus 44% [p=0.035])
Of the 25 non-responder patients at Week 120, six reverted to positive and
eight did not achieve culture conversion prior to the last assessment
Diacon AH, et al. N Engl J Med 2014;371:723–32
I
Personal notes
I joined the TMC C208 study team in 2009 as an
investigator in Stage 2.
We were blinded to active and placebo at the time
However, we could see from the clinical response who
got active drug
Study TMC207-C209
C209: Phase II, single-arm, open-label,
multicentre study
•
C209* included 233 adults with either newly or non-newly diagnosed confirmed smearpositive pulmonary MDR-TB disease, including
pre-XDR- and XDR-TB
Last study visit
120 weeks
(30 months)
Overall treatment phase
18–24 month total MDR-TB treatment
Open label
weeks
22 weeks
24 weeks
Screening
(N=294)
IBR + BDQ: 400 mg qd for 14
days, then 200 mg tiw
Post-investigational
treatment phase
≥6 months treatmentfree follow up
96-week follow-up
IBR alone
24-weeks (primary efficacy endpoint)
*NCT00910871
Pym A, et al. Int J Tuberc Lung Dis 2013;17 (Suppl 2):S236. OP-179-02
C209: conversion rates (MGIT) on
bedaquiline –
primary
Week
analysis
Median time to culture
conversion24
(mITT) mITT
= 57 days
Proportion of culture positive
1.0
0.8
0.6
50%
0.4
0.2
79.5% culture converted
0
BAS
4
8
12
Time (weeks)
16
The intersection of horizontal dotted line and each treatment arm
represents the median time to sputum conversion
20
24
Haxaire M, et al. Int J Tuberc Lung Dis 2011;14 Suppl 3:S58
C209: time to conversion by
subgroup Week 24 analysis
1.0
Time to culture conversion – end censored
Week 24 analysis
MDR-TB (n=93)
Pre-XDR-TB (n=44)
XDR-TB (n=36)
Proportion of culture positive
0.8
0.6
50%
0.4
55.6% response
rate
0.2
77.3% response
rate
87.1% response
rate
0
BAS
4
8
12
Time (weeks)
The intersection of horizontal dotted line and each treatment arm
represents the median time to sputum conversion
16
20
24
Haxaire M, et al. Int J Tuberc Lung Dis 2011;14 Suppl 3:S58
Registration of Bedaquiline
EU – March 2014
India – Jan 2015
Russia – October 2013
US – Dec 2012
SA – October 2014
Compassionate access / Extended access
program / Named patient program
Granting access to drugs prior to approval for patients
who have exhausted all alternative treatment
options and do not match clinical trial entry criteria.
Previous examples- Kaletra EAP, Tipranavir EAP,
intravenous oseltamivir, chemotherapeutic agents.
35
Methods
Pre-XDR and XDR TB patients at five approved sites
across South Africa were selected by pre-defined
criteria
BDQ Clinical Access Program (BCAP)
Cases were first presented to a national Clinical
Advisory Committee
Then, Janssen pharmaceutical approved BDQ with an
optimised background regimen.
MCC approval on a named-patient basis
Results
To date there are 12 approved sites in South
Africa
However ,Pre-XDR and XDR- TB patients
presented in this report are from five approved
sites
Up to 221 patients have been started on BDQ
Analysis presented here for 91 patients enrolled
by 15 July 2014
Data censored on 30 August 2014
Results-Baseline
Characteristics
Median Age :34,1 years ( IQR 25.7, 40.9)
Sex M: 56 (61.5%)
HIV infected : 55 (60.5%)
Median CD4+ : 249 (IQR 134; 356)
On LPV/r: 19 (34.5%)
On NVP 36 (65.5%)
Figure 1. Interim outcomes for XDR and pre XDR TB patients enrolled in National Bedaquiline
Clinical Access Programme in South Africa
Died
n=2
Completed 24
weeks BDQ
n=58
Defaulted n=1
On continuation
treatment
n=54
>24 weeks since
treatment start
n=60
Did not complete
BDQ
n=2
Enrolled, started on BDQ and
included in the analysis
n=91
33 XDR-TB
41 pre XDR (FLQ)
17 pre XDR (injectable)
Transferred out
n=1
Died
n=1
Defaulted
n=1
Culture negative at
start
n=6
<25 weeks since
treatment start
n=31
Still on treatment
n=31
Culture converted
n=10
Culture pending
n=15
BDQ: bedaquiline; XDR TB: extensively drug resistant TB; FLQ: fluoroquinolone
Culture negative at
start
n=15
Culture converted
n=33
Still culture positive
n=6
Results – culture conversion
Conclusion
The programme has allowed access to better
treatment and interim outcomes for (pre-)XDR
patients with otherwise limited options and
poor prognosis
Bedaquiline is now registered in South Africa
Objectives for the introduction of new drugs,
regimens and management for DR-TB within the SA
NTP
To ensure the appropriate selection of DR-TB patients
for new drugs, regimens and management.
To ensure the effective management of patients
currently or previously treated for DR TB.
To ensure appropriate monitoring and managing of
adverse events during DR-TB treatment and
effective pharmacovigilance
To ensure oversight and management from the
national level and implementation at provincial and
district levels
Effective management (1)
• DR TB Provincial Clinical Advisory Committees
• Multi-disciplinary
• Sub-committee of clinicians should be established
within the broader provincial committee.
– Appropriate clinical management of individual
MDR- and XDR-TB patients
– Use of salvage regimens in individual patients
with high-grade resistance
To ensure the appropriate selection
of patients for BDQ treatment
Access to bedaquiline for the first year of roll out will be limited
to the following 13 sites across all provinces:
– Eastern Cape - Fort Grey Hospital, Jose Pearson
– Free State – Dr S Moroka
– Gauteng - Sizwe Hospital, Helen Joseph Hospital
– KwaZulu Natal – King Dinizulu Hospital Complex
– Limpopo – FH Odendaal
– Mpumalanga – Witbank Hospital
– Northern Cape – Harry Surtie Hospital, West End
Hospital
– North West – Klerksdorp-Tshepong Hospital
– Western Cape – Brooklyn Chest Hospital, MSF
Khayelitsha CHC
Who is eligible for BDQ in the SA
NTP?
Patients ≥18 years of age
and
Laboratory-confirmed RR-TB (at least resistance to
RIF) by culture-based phenotypic drug sensitivity
testing or genotypic line probe assay or PCR testing
(Xpert MTB/RIF ) from both pulmonary and/or
extrapulmonary sites
and
No history or family history of QT prolongation or
baseline QTcF> 450 msec; and
Who is eligible for BDQ in the SA
NTP?
Drug resistance in addition to RR TB:
– XDR TB; or pre-XDR TB (resistant to either
fluoroquinolone or second line injectable drug);
or
– inhA and katG mutations;
Documented / recorded intolerance to 2nd line anti-TB
treatment at baseline or during RR TB treatment
History of, or surgical candidate for pneumonectomy or
lobectomy
Patients who meet the above criteria are not required for
review by the National or Provincial DR TB committees
Patients who meet the above criteria are not required for
review by the National or Provincial
DR TB committees
Which cases should be reviewed by the prior
to prescribing BDQ?
Patients does not have at least one other drug to which
their TB is susceptible or predicted susceptible (because
not previously exposed)
OR
Age < 18 years
OR
Pregnant
OR
Patients with MDR treatment failure (smear or culture
positive at 8 months on MDR treatment) without
proven 2nd line resistance.
How far have we got?
Only Free State and Mpumalanga have not
started
At last count over 1000 patients have got BDQ
12%
1%
8%
39%
40%
XDR TB
preXDR
inhA and KatG mutations
Intolerance or toxicity
Surgical candidate
Conclusions
For the first time in years, new drugs have been
added to routine management for MDR TB
The are new options on the horizon.