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

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.

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

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

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

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

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

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

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%)

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

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%)

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 [1.5-4.6] Increased liver enzymes (ALT increased or AST increased (≥ 1.1 x ULN))  8 22 2.1 [1.0-2.9] Peripheral Neuropathy  3.5 [1.3-5.0] No SAEs were reported in the first 6 months of treatment

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

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 [2.7-4.2] Prolonged (corrected) QT interval  3.2 [3.0-3.5] 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)

Pregnancy: patient characteristics 11 pregnancies in patient (N=8) or patient’s partner (N=3) Mother’s median age (yrs): 24 (range: 21 - 33) 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)

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