1. Session 4: Expanded indications for bedaquiline and delamanid
Accelerating TB Elimination through Access to Bedaquiline and Delamanid
October 12, 2017
K. J. Seung
Partners In Health

2. Introduction
As access to the new TB drugs expands, clinicians are choosing to use them in ways that are not included in current WHO recommendations due to lack of evidence
The most common such cases observed in the endTB are prescribing Bdq or Dlm:
For more than 24 weeks;
At the same time;
In children < 18 years of age; and
In pregnancy
The observational study is purely observational—there is no intervention.
These cases are not included in current WHO recommendations because of lack of evidence; endTB provides the opportunity to systematically collect evidence in such cases.

3. Methods
The following analyses are of subsets of the 687 patients who started a new TB drug (Bdq or Dlm) between 1 April 2015 and 31 October 2016

4. Extended use of Bdq or Dlm
Late treatment response
Patient still sputum culture-positive after 3 months or more of treatment with Bdq or Dlm and not meeting the criteria for treatment failure; and
The bacteriological (smear and/or culture) and clinical (weight) evolution indicates positive response to the treatment
Insufficient number of effective drugs in the treatment regimen
Less than 3 effective drugs in the regimen if Bdq or Dlm is stopped. If an injectable drug is present in the treatment regimen and it is planned to discontinue it, it should not be counted among these drugs
The paucity of effective drugs in the treatment regimen may be due to drug resistance pattern, adverse events or any other contraindications

5. Extended use of Bdq or Dlm
223 of 687 (32%) patients received more than 24 weeks of treatment:
157 (70%) received Bdq extension alone
38 (17%) received Dlm extension alone
28 (13%) received extension of both Bdq and Dlm

6. Extended use: patient characteristics (N=223)
Male
144 (65)
Median age [range]
36 [18 – 70]
Body mass index <18.5 (N=222)
80 (36)
Bilateral disease on x-ray (N=197)
142 (71)
Resistance (N=218)
         MDR or Xpert RR
         Pre-XDR (FQ-R)
         Pre-XDR (SLI-R) 
         XDR
         Other
59 (28)
35 (16)
11 (5)
104 (48)
9 (4)
Comorbidities
HIV (N=222)
Hepatitis C (N=211)
Diabetes (N=205)
23 (11)
17 (8)
Previous use of SLD (N=218)
156 (72)
OTHERS – what do we want to call these in the table
H(S) resistance (1)
HE(S) resistance (1)
R resistance with H susceptibility (3)
Other: 4

7. Extended use of Bdq or Dlm: safety
AEI (N=91)
0 to 6 months of treatment
6 to 12 months of treatment
N​ events
%​ of pts
% in grade 3 or 4​
N events​
Increased liver enzymes (ALT increased or AST increased (≥ 1.1 x ULN))​ 55
24.4
5.4 32
23.0
Prolonged(corrected) QT interval​ 38
16.9
2.6 25
18.0
8.0
Peripheral neuropathy​ 26
11.6
15.4 9
6.5
11.1
Acute kidney injury 22
9.8
0.0 17
12.2
AEI = Adverse Event of Interest

8. Extended use of Bdq or Dlm: safety
SAE (=91)
0 to 6 months of treatment
6 to 12 months of treatment N​ %​
Patients with ≥ 1 SAE 14
15.4 13
14.3
Total number of SAE 17 20
Electrocardiogram QT Corrected Interval 3
17.7 1
5.0
Increased liver enzymes
5.9
Acute kidney injury
SAE = Serious Adverse Event

9. Combined Bdq / Dlm Use
46 patients ever received Dlm and Bdq in combination
22 (48%) started Dlm and Bdq combination within 7 days of each other 
24 (52%) started Dlm and Bdq sequentially 
Dlm added to Bdq: 18 (75%)
Bdq added to Dlm: 6 (25%)

10. Combined use: patient characteristics (N=46)
Male
29 (63)
Median age [range]
37 [17-63]
Body mass index <18.5
22 (49)
Bilateral disease on x-ray (N=45)
33 (73)
Resistance (N=45)
         MDR
         Pre-XDR (FQ-R)
         Pre-XDR (SLI-R) 
         XDR
         Other
4 (9)
8 (18)
2 (4)
30 (67)
1 (2)
Comorbidities
HIV (N=45)
Hepatitis C (N=44)
Diabetes (N=45)
12 (27)
3 (7)
This person is Rif R; FQ R; H sens

11. Conversion with combined use of Bdq, Dlm
46 with concomitant use
22 (48%) started Bdq and Dlm at the same time
11 (50%) with positive baseline culture
8 converted
73% (95% CI: 39-94%)

12. Efficacy and safety of combined use with Bdq and Dlm
Includes 22 patients who started Bdq and Dlm together
AEI term​
(37 Aes of interest in the first 6 mos) N​ %​
Number in grade 3 or 4​
Median [IQR] time to AEI​
Prolonged (corrected) QT interval  9 24 1
3.0 [ ]
Increased liver enzymes (ALT increased or AST increased (≥ 1.1 x ULN))  8 22
2.1 [ ]
Peripheral Neuropathy 
3.5 [ ]
No SAEs were reported in the first 6 months of treatment

13. Children: patient characteristics (N=8)
Male
4 (50)
Median age [range]
16 [14-17]
Body mass index <18.5
1 (13)
Bilateral disease on x-ray (N=7)
2 (29)
Resistance
         MDR
         Pre-XDR (FQ-R)
         Pre-XDR (SLI-R) 
         XDR
         Other
2 (25)
HIV
Culture positive at the start of new drug (N=7)
Molly check Ns on all

14. Children: efficacy and safety
Among culture positive (N=1)
Culture conversion at 6 months
1 (100%)
AEI term​ (7 AE of interest in the first 6 months) N​ %​
Number in grade 3 or 4​
Median[IQR] time to AEI​
Anemia 2
28.6
3.5 [ ]
Prolonged (corrected) QT interval 
3.2 [ ]
Increased liver enzymes (ALT increased or AST increased (≥ 1.1 x ULN))  1
14.3
0.9
Hypokalemia (K ≤ 3.4 mEq/L)
2.1
Peripheral Neuropathy
3.0
4 SAEs were reported in the first 6 months among 3 children
Death, Headache (Grade 3), Vomiting (Grade 1), Dizziness (Grade 1)

15. Pregnancy: patient characteristics
11 pregnancies in patient (N=8) or patient’s partner (N=3)
Mother’s median age (yrs): 24 (range: )
Timing of new drug treatment initiation
Prior to pregnancy: 11
Median time on Tx (mos): 9.46 (range: 0.83 – 19.8)
Mother’s medical history mostly unreported
Information missing for 4 cases
Information available for 4 cases
4 mothers with medical history reported had prior pregnancies (1-2); 3 mothers have living children (1-2)
11 pregnancies occurred while on treatment – includes both patients and partners
Mean time on Tx: 9.16 months
Median time on Tx: 9.46 months
Range: 0.83 – 19.8 months
Age of 1 mother unknown (partner of patient)

16. Exposure via mother (N=8) Exposure via father (N=3)
Pregnancy: outcomes
Exposure via mother (N=8)
Exposure via father (N=3)
TB regimen maintained 6
N/A
TB treatment modified 1
Unknown 3
Exposure via mother:
Most frequently used drugs Bdq and Lzd
1 Dlm-based regimen maintained contingent on termination of pregnancy
Treatment modifications:
TB regimen maintained: 6
All 6 patients had induced abortions
TB treatment modified: 1
Birth outcome unknown
Unknown: 1
Abortion induced
It is likely that the TB treatment was maintained, but this has not been confirmed.
Outcomes:
7 induced abortions
1 pregnancy outcome unreported
Exposure via father:
2 pregnancies ongoing