Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Molloy SF, Kanyama C, Heyderman RS, et al. Antifungal combinations for treatment of cryptococcal meningitis in Africa. N Engl J Med 2018;378: DOI: /NEJMoa

2 SUPPLEMENTARY APPENDIX TABLE OF CONTENTS ACTA Trial Team... 2 Table S1. Baseline characteristics of study participants by AmB partner treatment (N=453)... 3 Table S2. Baseline characteristics of study participants by 5 arms (N=678)... 5 Table S3. Time to event outcomes by 3 treatment regimens (Intention-to-treat (ITT), unadjusted analysis; N=678)... 7 Table S4. Mortality by 3 treatment regimens, AmB partner treatment and 5 arms (Per protocol (PP), unadjusted analysis; N=662)... 8 Table S5. Mortality by 3 treatment regimens, AmB partner treatment and 5 arms (Intention-to-treat (ITT), adjusted analysis; N=678)... 9 Table S6A. Sensitivity analysis* for all-cause mortality at 2 and 10 weeks by 3 treatment regimens (N=678) Table S6B. Sensitivity analysis* for all-cause mortality at 2 and 10 weeks by AmB partner treatment (N=678) Table S6C. Sensitivity analysis* for all-cause mortality at 2 and 10 weeks by 5 arms (N=678) Table S7. Time to event outcomes by 5 arms (Intention-to-treat (ITT), unadjusted analysis, reference group: ; N=678) Table S8A. Comparison of rate of fungal clearance by 3 treatment regimens using linear regression13 Table S8B. Comparison of rate of fungal clearance by AmB partner treatment using linear regression Table S8C. Comparison of rate of fungal clearance by 5 arms using linear regression Table S9A. Safety data: lab defined and clinical adverse events* (AEs) by 5 arms (N=677 Ω ) Table S9B. Safety data: lab defined and clinical adverse events* (AEs) by AmB partner treatment (N=453) Figure S1. Difference in all-cause mortality between ART-naïve participants and those previously exposed to ART

3 ACTA Trial Team In addition to the authors, the following were members of the ACTA trial team: Malawi-Liverpool-Wellcome Trust/University of Malawi/Queen Elizabeth hospital, Blantye, Malawi W. Chimanganga, E. Chilima, E. Dziwani, E. Gondwe, P. Goodson, C. Jassi, C. Kukacha, L. Keyla, M. Likwinj, D. Ming, D. Segula, A. Singimi, S. Miyango, V. Mwloza, L. Matandika, N. Mthunthama, J. Ndaferankhande, C. Rothe, C. Sambakunsi, F. Shumba. General Hospital, Douala, Cameroon E. Bagna, F. Bella, A. Dang, J. Epupa, H. Essaka, G. Goula, H. Luma, A. Ngoula. UNC Project, Kamuzu Central Hospital, Lilongwe, Malawi T. Banda, B. Banda, T. Chikaonda, M. Chikasema, M. Chipeta, N. Chome, C. Kanyemba, E. Kasonkanji, E. Kumwenda, W. Kumwenda, W. Mhango, L. Msumba, P. Mwangomba, F. Namaluweso, J. Phulusa, I. Shumba, D. Sichali. Institute for Medical Research and Training, University Teaching Hospital, Zambia D. Chanda, A. Chansa, E. Chikatula, Y. Kakusa, M. Mputu, M. Mukasine, J. Mwaba, W. Mwambazi, L. Mwanamoonga, A. Mweeba, J. Nglube, M. Sichone, J. Silumbe, A. Tande. National Institute Medical Research, Muhimbili Medical Research Centre, Dar es Salaam, Tanzania - A. Abdallah, D. Buma, A.A. Chande, E. Diarz, M. Hassan, J.M. Kalabashanga, R. Kalinga, D. Kileo, A. Kimambo, R. Lawrence, T. Massawa, M. Mganga, S. Mamboya, M.M. Nyange, K. Okeng o, R. Simbaulanga, J. Rugemalila, I.B. Tarimo. Hȏpital Central Yaoundé/Site ANRS Cameroun - S. Kouala-Shiro, E. Delaporte, M. Alma, R. Dombu, R.E. Djoukwe, C. Embolo, S. Le Gac, A. Kamdem, G. Mounpou, E.P. Owono, E. Pasquier, E. Sonkeng, S. Tongo, P. Vigne, M. Wodo. Dignitas International, Zomba Central Hospital, Zomba, Malawi - G. Kaphale, E. Nyondo, A. Jusu, K. Kalima, Y. Mataka, C. Khoriyo, L. Silwamba. Centre for Global Health, Institute for Infection and Immunity, St George s University of London, London, United Kingdom - S. Abdelmalik, S. Burton London School of Hygiene and Tropical Medicine, London, United Kingdom - V. Simms. 2

4 Table S1. Baseline characteristics of study participants by AmB partner treatment (N=453) Baseline characteristics AmB AmB (n=228) Male sex no. (%) 134 (59.6) 137 (60.1) Age years Median (IQR) 39.0 ( ) 38.0 ( ) Reported ART exposure no. (%) ψ 115 (51.1) 138 (60.5) Weight (kg) Φ Median (IQR) ( ) ( ) Current headache no. (%) 222 (98.7) 225 (98.7) Duration of headache (days) Median (IQR) 14.0 ( ) 14.0 ( ) Seizures within 72hrs of enrolment no. (%) 42 (18.7) 37 (16.2) Current fever no. (%) 112 (49.8) 106 (46.5) Current visual loss no. (%) 16 (7.1) 23 (10.1) Cranial-nerve palsy (any) no. (%) 17 (7.6) 19 (8.3) Previous medical history of TB no./total no. (%) 58 (25.8) 62 (27.2) Glasgow coma score < 15 no. (%) 57 (25.3) 53 (23.2) Abnormal mental status* no. (%) 103 (45.8) 94 (41.2) CSF fungal count (log 10CFU/ml) ξ Median (IQR) 4.9 ( ) 5.1 ( ) CSF opening pressure β (cm ) Median (IQR) 25.0 ( ) 25.0 ( ) CSF opening pressure β (cm ) >30 81 (38.6) 77 (35.6) CSF white-cell count (cells/mm 3 ) Ω Median (IQR) 4.0 ( ) 3.0 ( ) CSF glucose level (mmol/l) ϑ Median (IQR) 2.0 ( ) 2.00 ( ) CSF protein level (mg/dl) ** Median (IQR) ( ) 98.0 ( ) Hemoglobin (g/dl) Median (IQR) 10.8 ( ) 11.1 ( ) Creatinine (mg/dl) Ξ Median (IQR) 0.7 ( ) 0.7 ( ) Baseline CD4 count (cells/ul) ς Median (IQR) 29.0 ( ) 24.0 ( ) ψ Considering only patients enrolled from the ART amendment proportions were: 53.0% in group A and 63.0% in group B. Data were missing for 8 patients in AmB+FLU and 9 patients in AmB+5FC. Φ Data were missing for 4 patients in AmB+FLU and 7 patients in AmB+5FC Data were missing for 3 patients in AmB+FLU and 3 patients in AmB+5FC 3

5 * Abnormal mental status is defined as having 1 of the following symptoms in the last 72hrs: Drowsiness, behavioral change and/or Seizures ξ Data were missing for 7 patients in AmB+FLU and 3 patients in AmB+5FC β Data were missing for 15 patients in AmB+FLU and 12 patients in AmB+5FC Ω Data were missing for 12 patients in AmB+FLU and 6 patients in AmB+5FC ϑ Data were missing for 31 patients in AmB+FLU and 19 patients in AmB+5FC ** Data were missing for 30 patients in AmB+FLU and 25 patients in AmB+5FC Data were missing for 1 patient in AmB+5FC Ξ Data were missing for 2 patients in AmB+5FC ς Data were missing for 15 patients in AmB+FLU and 15 patients in AmB+5FC 4

6 Table S2. Baseline characteristics of study participants by 5 arms (N=678) Baseline characteristics (n=111) (n=113) (n=114) (n=115) Male sex no. (%) 119 (52.9) 67 (60.4) 70 (61.9) 67 (58.8) 67 (58.3) Age years Median (IQR) 36.0 ( ) 39.0 ( ) 38.0 ( ) 37.5 ( ) 37.0 ( ) Reported ARV exposure no./total no. (%) ψ 128 (56.9) 54 (48.6) 65 (57.5) 61 (53.5) 73 (63.5) Weight (kg) Φ Median (IQR) 50.0 ( ) 53.5 ( ) 53.0 ( ) 51.3 ( ) 50.0 ( ) Current headache no. (%) 221 (98.2) 109 (98.2) 112 (99.1) 113 (99.1) 113 (98.3) Duration of headache (days) Median (IQR) 14 (7-21) 14 (7-21) 13 (7-21) 14 (7-28) 14 (7-28) Seizures within 72hrs of enrolment no. (%) 40 (17.8) 23 (20.7) 20 (17.7) 19 (16.7) 17 (14.8) Current fever no. (%) 119 (52.9) 54 (48.6) 49 (43.4) 58 (50.9) 57 (49.6) Current visual loss no. (%) 17 (7.6) 8 (7.2) 9 (8.0) 8 (7.0) 14 (12.2) Cranial-nerve palsy (any) no. (%) 17 (7.6) 7 (6.3) 6 (5.3) 10 (8.8) 13 (11.3) Previous medical history of TB no./total no. (%) 63 (28.1) 31 (27.9) 29 (25.7) 27 (23.7) 33 (28.7) Glasgow coma score < 15 no. (%) 53 (23.6) 27 (24.3) 19 (16.8) 30 (26.3) 34 (29.6) Abnormal mental status* no. (%) 101 (44.9) 51 (45.9) 39 (34.5) 52 (45.6) 55 (47.8) CSF fungal count (log 10CFU/ml) ξ Median (IQR) 5.0 ( ) 4.9 ( ) 5.1 ( ) 5.0 ( ) 5.0 ( ) CSF opening pressure β (cm) Median (IQR) 22 (13-35) 23 (13-35) 25 (12-40) 26 (16-38) 24 (15-36) CSF opening pressure β (cm) >30 69 (31.7) 39 (37.1) 39 (36.8) 42 (40.0) 38 (34.5) CSF white-cell count (cells/mm 3 ) Ω Median (IQR) 4.0 ( ) 5.0 ( ) 3.5 ( ) 4. 0( ) 1.5 ( ) CSF glucose level (mmol/l) ϑ Median (IQR) 2.0 ( ) 2.0 ( ) 2.0 ( ) 2.0 ( ) 1.9 ( ) CSF protein level (mg/dl) ** Median (IQR) ( ) ( ) ( ) ( ) ( ) Hemoglobin (g/dl) Median (IQR) 10.7 ( ) 10.7 ( ) 11.2 ( ) 11.1 ( ) 10.8 ( ) Creatinine (mg/dl) Ξ Median (IQR) 0.7 ( ) 0.8 ( ) 0.8 ( ) 0.7 ( ) 0.7 ( ) Baseline CD4 count (cells/micro litre) ς Median (IQR) 25.0 ( ) 28.5 ( ) 24.5 ( ) 29.5 ( ) 22.0 ( ) ψ Considering only patients enrolled from the ART amendment proportions were: 60.1% in oral, 50.0% in +FLU, 60.2% in +5FC, 55.0 in +FLU and 65.8 in +5FC. 5

7 Φ Data were missing for 5 patients in oral, 3 patients in +FLU, 3 patients in +5FC, 1 patient in 2 weeks AmB+FLU and 4 patients in +5FC. Data were missing for 4 patients in oral, 2 patients in +FLU, 1 patient in +5FC, 1 patient in 2 weeks AmB+FLU and 2 patients in +5FC. * Abnormal mental status is defined as having 1 of the following symptoms in the last 72hrs: Drowsiness, behavioral change and/or Seizures ξ Data were missing for 10 patients in oral, 1 patient in +FLU, 1 patient in +5FC, 6 patients in 2 weeks AmB+FLU and 2 patients in +5FC. β Data were missing for 7 patients in oral, 6 patients in +FLU, 7 patients in +5FC, 9 patients in 2 weeks AmB+FLU and 5 patients in +5FC. Ω Data were missing for 4 patients in oral, 5 patients in +FLU, 3 patients in +5FC, 7 patients in 2 weeks AmB+FLU and 3 patients in +5FC. ϑ Data were missing for 27 patients in oral, 15 patients in +FLU, 9 patients in +5FC, 16 patients in 2 weeks AmB+FLU and 10 patients in +5FC. ** Data were missing for 24 patients in oral, 12 patients in +FLU, 11 patients in +5FC, 18 patients in 2 weeks AmB+FLU and 14 patients in +5FC. Data were missing for 1 patient in oral, 1 patient in +5FC and 1 patient in +5FC. Ξ Data were missing for 4 patients in oral, 1 patient in +5FC and 1 patient in +5FC. ς Data were missing for 16 patients in oral, 3 patients in +FLU, 9 patients in +5FC, 12 patient in 2 weeks AmB+FLU and 6 patients in +5FC. 6

8 Table S3. Time to event outcomes by 3 treatment regimens (Intention-to-treat (ITT), unadjusted analysis; N=678) 2 week mortality (13.2 to 23.3) (n=224) (16.5 to 27.4) (n=229) (16.1 to 26.7) Hazard Ratio vs vs (log-rank test) 0.82 (0.54 to 1.25) 1.01 (0.68 to 1.51) week mortality (19.2 to 30.5) (23.6 to 35.5) (27.5 to 39.7) 0.71 (0.50 to 1.00) 0.86 (0.62 to 1.20) week mortality (28.9 to 41.3) (30.0 to 42.7) (33.5 to 46.2) 0.83 (0.61 to 1.13) 0.89 (0.66 to 1.21)

9 Table S4. Mortality by 3 treatment regimens, AmB partner treatment and 5 arms (Per protocol (PP), unadjusted analysis; N=662) A Mortality at 2 weeks (n=220) (13.1 to 23.3) (n=220) (15.6 to 26.3) (n=222) (16.2 to 27.0) Risk difference (95% 2-sided CI) vs vs ( to 4.00) (-8.34 to 6.92) B 10 week mortality AmB (n=220) (38.0 to 51.2) AmB (n=222) (24.3 to 36.4) Hazard Ratio AmB vs AmB (log-rank test) 0.60 (0.44 to 0.83) Mortality at 4 weeks Mortality at 10 weeks (18.9 to 30.2) (28.7 to 41.3) (22.7 to 34.7) (29.3 to 42.0) (27.6 to 40.0) (32.8 to 45.7) ( to -0.81) ( to 3.48) ( to 4.81) ( to 5.28) 2 week mortality 4 week mortality (20.5 to 32.2) (31.3 to 44.1) (11.4 to 21.1) (19.2 to 30.6) 0.58 (0.38 to 0.88) (0.42 to 0.84) C 10 week mortality (n=220) (28.7 to 41.3) (n=108) (38.7 to 57.6) (n=112) (15.6 to 31.4) (n=112) (32.0 to 50.3) (n=110) (28.2 to 46.3) Hazard Ratio (Reference group: ) (log-rank test) 0.89 (0.61 to 1.30) 1.43 (0.94 to 2.16) 0.55 (0.34 to 0.90) 1.12 (0.73 to 1.71) week mortality 4 week mortality (13.1 to 23.3) (18.9 to 30.2) (22.7 to 40.2) (31.5 to 50.0) (5.0 to 16.5) (10.1 to 24.1) (13.8 to 29.0) (26.0 to 43.6) (14.1 to 29.5) (24.0 to 41.5) 0.79 (0.48 to 1.33) 1.51 (0.89 to 2.57) 0.45 (0.22 to 0.90) 0.96 (0.54 to 1.70) (0.46 to 1.09) 1.34 (0.86 to 2.10) 0.46 (0.26 to 0.81) 1.06 (0.67 to 1.67) Panel A. Mortality and rate of fungal clearance by 3 treatment regimens (PP, unadjusted analysis with loss to follow up included as alive) Panel B. Mortality and rate of fungal clearance by AmB partner treatment (Time to event. PP, unadjusted analysis with loss to follow up included as alive) Panel C. Mortality and rate of fungal clearance by 5 arms (Time to event. PP, unadjusted analysis with loss to follow up included as alive). 8

10 Table S5. Mortality by 3 treatment regimens, AmB partner treatment and 5 arms (Intention-to-treat (ITT), adjusted analysis; N=678) A Mortality at 2 weeks Mortality at 4 weeks Mortality at 10 weeks (13.2 to 23.3) (19.2 to 30.5) (28.9 to 41.3) (n=224) (16.5 to 27.4) (23.6 to 35.5) (30.0 to 42.7) (n=229) (16.1 to 26.7) (27.5 to 39.7) (33.5 to 46.2) Risk difference (90% 2-sided CI) vs vs 0.54 (-4.92 to 6.00) 2.24 (-3.53 to 8.0) ( to 0.06) (-9.90 to 4.10) ( to 4.29) (-9.81 to 4.81) *Adjusted for site, age, sex, Glasgow Coma Score (GCS), CD4 count, CSF fungal burden at baseline and ART status at baseline C 10 week mortality Probability of death (28.9 to 41.3) (n=111) (39.4 to 57.9) (n=113) (16.2 to 32.1) (n=114) (32.3 to 50.4) B (n=115) (29.4 to 47.2) 10 week mortality Probability of death 2 week mortality Probability of death 4 week mortality Probability of death AmB (38.5 to 51.5) (21.3 to 32.9) (31.9 to 44.6) AmB (n=228) (25.3 to 37.3) (11.5 to 21.1) (19.4 to 30.7) Hazard Ratio AmB vs AmB (log-rank test) 0.56 (0.41 to 0.77) (0.30 to 0.75) (0.39 to 0.79) *Adjusted for site, age, sex, Glasgow Coma Score (GCS), CD4 count, CSF fungal burden at baseline, ART status at baseline and length of AmB treatment Hazard Ratio (Reference group: ) (log-rank test) 0.91 (0.63 to 1.33) 1.57 (1.05 to 2.37) 0.59 (0.36 to 0.96) 1.15 (0.76 to 1.75) week mortality Probability of death 4 week mortality Probability of death (13.2 to 23.3) (19.2 to 30.5) (23.7 to 41.1) (32.3 to 50.6) (5.7 to 17.5) (10.7 to 24.9) (14.3 to 29.5) (26.3 to 43.8) *Adjusted for site, age, sex, Glasgow Coma Score (GCS), CD4 count, CSF fungal burden at baseline and ART status at baseline (13.4 to 28.3) (23.6 to 40.7) 0.91 (0.54 to 1.53) 1.98 (1.15 to 3.41) 0.58 (0.29 to 1.16) 1.08 (0.61 to 1.93) (0.51 to 1.19) 1.59 (1.01 to 2.48) 0.54 (0.31 to 0.94) 1.15 (0.73 to 1.81) <0.001 Panel A. Mortality and rate of fungal clearance by 3 treatment regimens (ITT, adjusted analysis with loss to follow-up included as alive) Panel B. Mortality and rate of fungal clearance by AmB partner treatment (Time to event, ITT, adjusted analysis) Panel C. Mortality and rate of fungal clearance by 5 arms (Time to event. ITT, adjusted analysis). 9

11 Table S6A. Sensitivity analysis* for all-cause mortality at 2 and 10 weeks by 3 treatment regimens (N=678) 2 week mortality Type of sensitivity analysis (n=224) (n=229) Risk difference (90% 2-sided CI) vs vs (%) Imputing LTFU as alive 41 (18.2) 49 (21.9) 49 (21.4) (-9.32 to 2.97) 0.48 (-5.89 to 6.84) Imputing LTFU by the worstcase scenario 41 (18.2) 50 (22.3) 49 (21.4) (-9.32 to 2.97) 0.92 (-5.46 to 7.31) 10 week mortality (%) Imputing LTFU as alive 79 (35.1) 81 (36.2) 91 (39.7) ( to 2.84) ( to 3.92) Imputing LTFU by the worstcase scenario *Sensitivity analysis was unadjusted and performed on ITT population 79 (35.1) 83 (37.1) 93 (40.6) ( to 1.98) ( to 3.97) Table S6B. Sensitivity analysis* for all-cause mortality at 2 and 10 weeks by AmB partner treatment (N=678) 10 week mortality Type of sensitivity analysis AmB AmB (n=228) Hazard Ratio AmB vs AmB (log-rank test) (%) No imputation 101 (44.9) 71 (31.1) 0.62 (0.45 to 0.84) Imputation by worst-case scenario 103 (45.8) 73 (32.0) 0.62 (0.46 to 0.84) week mortality (%) No imputation 61 (27.1) 37 (16.2) 0.56 (0.37 to 0.85) Imputation by worst-case scenario *Sensitivity analysis was unadjusted and performed on ITT population 61 (27.1) 38 (16.6) 0.58 (0.38 to 0.87)

12 Table S6C. Sensitivity analysis* for all-cause mortality at 2 and 10 weeks by 5 arms (N=678) 10 week mortality (%) No imputation 79 Imputation by worst-case scenario (35.1) 79 (35.1) (n=111) 54 (48.6) 54 (48.6) 1 week AmB (n=113) 27 (23.9) 29 (25.7) 2 weeks AmB (n=114) 47 (41.2) 49 (43.0) 2 weeks AmB (n=115) 44 (38.3) 44 (38.3) 0.87 (0.60 to 1.27) 0.87 (0.60 to 1.27) Hazard Ratio (Reference group: ) 1.42 (0.95 to 2.12) 1.42 (0.95 to 2.13) 0.56 (0.35 to 0.91) 0.60 (0.37 to 0.96) 2 weeks AmB 1.10 (0.73 to 1.67) 1.15 (0.76 to 1.73) (log-rank test) week mortality (%) No imputation 41 (18.2) 36 (32.4) 13 (11.5) 25 (21.9) 24 (20.9) 0.84 (0.50 to 1.39) 1.64 (0.97 to 2.78) 0.51 (0.26 to 1.00) 1.03 (0.59 to 1.82) Imputation by worst-case scenario 41 (18.2) 36 (32.4) 14 (12.4) 25 (21.9) 24 (20.9) 0.84 (0.50 to 1.39) 1.64 (0.97 to 2.78) 0.55 (0.28 to 1.06) 1.03 (0.58 to 1.82) *Sensitivity analysis was unadjusted and performed on ITT population 11

13 Table S7. Time to event outcomes by 5 arms (Intention-to-treat (ITT), unadjusted analysis, reference group: ; N=678) (n=111) (n=113) (n=114) (n=115) Hazard Ratio (Reference group: ) (log-rank test) 10 week mortality Probability of death (28.9 to 41.3) (39.4 to 57.9) (16.2 to 32.1) (32.3 to 50.4) (29.4 to 47.2) 1.56 (1.01 to 2.42) 2.54 (1.60 to 4.05) 1.97 (1.22 to 3.17) 1.79 (1.10 to 2.89) week mortality Probability of death (13.2 to 23.3) (23.7 to 41.1) (5.7 to 17.5) (14.3 to 29.5) (13.4 to 28.3) 1.65 (0.88 to 3.10) 3.25 (1.71 to 6.16) 2.04 (1.04 to 4.00) 1.98 (1.00 to 3.90) week mortality Probability of death (19.2 to 30.5) (32.3 to 50.6) (10.7 to 24.9) (26.3 to 43.8) (23.6 to 40.7) 1.49 (0.89 to 2.48) 2.83 (1.67 to 4.81) 2.20 (1.28 to 3.78) 2.01 (1.16 to 3.48) <

14 Table S8A. Comparison of rate of fungal clearance by 3 treatment regimens using linear regression CSF fungal clearance rate (n=224) (n=229) No. patients vs vs Difference in mean clearance rate Log10 CFU/ml/day mean (SD) (0.18) (0.24) (0.25) 0.16 (0.12 to 0.21) < (-0.02 to 0.07) 0.37 Table S8B. Comparison of rate of fungal clearance by AmB partner treatment using linear regression CSF fungal clearance rate AmB AmB (n=228) No. patients AmB vs AmB Difference in mean clearance rate Log10 CFU/ml/day mean (SD) (0.23) (0.25) (-0.15 to -0.05) <0.001 Table S8C. Comparison of rate of fungal clearance by 5 arms using linear regression 1 week AmB (n=111) 1 week AmB (n=113) 2 weeks AmB (n=114) 2 weeks AmB (n=115) CSF fungal clearance rate Difference in mean clearance rate, (Reference group: ) No. patients Log10 CFU/ml/day mean (SD) (0.18) (0.23) (0.25) (0.24) (0.25) 0.23 (0.17 to 0.28) < (0.06 to 0.19) < (-0.02 to 0.11) (0.05 to 0.18) <

15 Table S9A. Safety data: lab defined and clinical adverse events* (AEs) by 5 arms (N=677 Ω ) Event Any adverse event At least 1 Grade 3/4 event no. patients (%) (n=111) (n=113) (n=114) (n=115) 151 (67.1) 85 (76.6) 70 (61.9) 97 (85.1) 89 (78.1) Grade 3 60 (26.7) 28 (25.2) 32 (28.3) 36 (31.6) 38 (33.3) Grade 4 69 (30.7) 36 (32.4) 32 (28.3) 48 (42.1) 32 (28.1) Anemia no. patients (%) Grade 3** 9 (4.0) 15 (13.5) 8 (7.1) 20 (17.5) 21 (18.4) Grade 4 ς 2 (0.9) 9 (8.1) 2 (1.8) 8 (7.0) 12 (10.5) Change in hemoglobin to day 14 (g/dl) ψ Median (IQR) -0.4 (-0.9 to 0.3) Neutropenia no. patients (%) -1.7 (-2.7 to -0.9) -1.4 (-2.2 to -0.7) -2.6 (-3.6 to -1.5) -2.6 (-3.2 to -1.7) Grade 3** 15 (6.7) 5 (4.5) 10 (8.8) 9 (7.9) 9 (7.9) Grade 4 ς 8 (3.6) 2 (1.8) 1 (0.9) 1 (0.9) 3 (2.6) Hypokalemia no. patients (%) Grade 3** 3 (1.3) 5 (4.5) 9 (8.0) 8 (7.0) 7 (6.1) Grade 4 ς 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.9) 0 (0.0) Grades 3 and 4 3 (1.3) 5 (4.5) 9 (8.0) 9 (7.9) 7 (6.1) Thrombocytopenia no. patients (%) Grade 3** 2 (0.9) 4 (3.6) 1 (0.9) 1 (0.9) 2 (1.8) Grade 4 ς 4 (1.8) 0 (0.0) 2 (1.8) 1 (0.9) 0 (0.0) Elevated ALT no. patients (%) Grade 3** 6 (2.7) 2 (1.8) 5 (4.4) 5 (4.4) 2 (1.8) Grade 4 ς 0 (0.0) 0 (0.0) 1 (0.9) 1 (0.9) 0 (0.0) Elevated Creatinine no. patients (%) Grade 3** 6 (2.7) 10 (9.0) 4 (3.5) 11 (9.6) 6 (5.3) Grade 4 ς 5 (2.2) 1 (0.9) 0 (0.0) 3 (2.6) 1 (0.9) Change in creatinine to day 14 (µmol/l) β Median (IQR) 0 (-8.8 to 13.0) 13.0 (0 to 35.0) 15.0 (0.5 to 32.5) 43.5 (17.7 to 88.0) 29.1 (8.8 to 61.0) 14

16 Event Pneumonia (n=111) (n=113) (n=114) (n=115) Grades 3 and 4 4 (1.8) 5 (4.5) 1 (0.9) 7 (6.1) 3 (2.6) Diarrhoea/vomiting Grades 3 and 4 6 (2.7) 2 (1.8) 0 (0.0) 1 (0.9) 3 (2.6) Bacteraemia/Sepsis Grades 3 and 4 10 (4.4) 8 (7.2) 2 (1.8) 12 (10.5) 6 (5.3) Other Grades 3 and (53.3) 61 (55.0) 64 (56.6) 81 (71.1) 67 (58.8) * Within 21 days from randomisation Ω 1 patient was excluded from the safety analysis as they died after randomisation but prior to receiving study medication The total number of Grade 3 or Grade 4 AEs was 377 in oral, 234 in +FLU, 231 in in +5FC, 341 in +FLU and 318 in +5FC ** Grade 3 AE definitions: Anemia: g/dl; Neutropenia: /mm 3 ; Hypokalemia: mmol/l; Thrombocytopenia: 25,000-49,999/mm 3 ; Elevated ALT: U/L; Creatinine rise: mg/dl ς Grade 4 definitions: Anemia: <6.5 g/dl; Neutropenia: <500/mm 3 ; Hypokalemia: <2.0 mmol/l; Thrombocytopenia: <25,000/mm 3 ; Elevated ALT: >350 U/L; Creatinine rise: >4.55 mg/dl ψ Data were missing for 35 patients in oral, 34 for patients in +FLU, 15 patients in +5FC, 16 patients in +FLU and 25 patients in +5FC. β Data were missing for 34 patients in oral, 33 patients in +FLU, 13 patients in +5FC, 19 patients in +FLU and 21 patients in +5FC 15

17 Table S9B. Safety data: lab defined and clinical adverse events* (AEs) by AmB partner treatment (N=453) Event Any adverse event AmB AmB (n=228) At least 1 Grade 3/4 event no. patients (%) 148 (65.8) 134 (59.0) Grade 3 64 (28.4) 70 (30.8) Grade 4 84 (37.3) 64 (28.2) Anemia no. patients (%) Grade 3** 34 (15.1) 26 (11.5) Grade 4 ς 17 (7.6) 14 (6.2) Change in hemoglobin to day 14 g/dl ψ Median (IQR) -2.2 (-3.9 to - 1.3) Neutropenia no. patients (%) -2.1 (-3.2 to - 1.1) Grade 3** 13 (5.8) 18 (7.9) Grade 4 ς 3 (1.3) 4 (1.8) Hypokalemia no. patients (%) Grade 3** 13 (5.8) 16 (7.0) Grade 4 ς 1 (0.4) 0 (0.0) Thrombocytopenia no. patients (%) Grade 3** 5 (2.2) 3 (1.3) Grade 4 ς 1 (0.4) 2 (0.9) Elevated ALT no. patients (%) Grade 3** 7 (3.1) 6 (2.6) Grade 4 ς 1 (0.4) 1 (0.4) Creatinine rise no. patients (%) Grade 3** 19 (8.4) 10 (4.4) Grade 4 ς 4 (1.8) 1 (0.4) Change in creatinine to day 14 µmol β Median (IQR) Pneumonia 29.0 (8.8 to 59.0) 18.0 (5.0 to 44.4) Grades 3 and 4 5 (2.2) 4 (1.8) Diarrhoea/vomiting Grades 3 and 4 3 (1.3) 2 (0.9) Bacteraemia/Sepsis Grades 3 and 4 16 (7.1) 7 (3.1) Other Grades 3 and (63.1) 131 (57.7) * Within 21 days from randomisation The total number of Grade 3 or Grade 4 AEs was 575 in AmB+FLU and 549 in AmB+5FC 16

18 ** Grade 3 AE definitions: Anemia: g/dl; Neutropenia: /mm 3 ; Hypokalemia: mmol/l; Thrombocytopenia: 25,000-49,999/mm 3 ; Elevated ALT: U/L; Creatinine rise: mg/dl ς Grade 4 definitions: Anemia: <6.5 g/dl; Neutropenia: <500/mm 3 ; Hypokalemia: <2.0 mmol/l; Thrombocytopenia: <25,000/mm 3 ; Elevated ALT: >350 U/L; Creatinine rise: >4.55 mg/dl ψ Data were missing for 52 patients in AmB+FLU and 41 patients in AmB+5FC β Data were missing for 34 patients in AmB+FLU and 34 patients in AmB+5FC 17

19 Figure S1. Difference in all-cause mortality between ART-naïve participants and those previously exposed to ART 18