Supplement: Tables and Figures Supplement Table 1. Baseline Characteristics by Study and Efavirenz Assignment

Supplement Table 2. Baseline Psychoactive Medications by Efavirenz Assignment*

Supplement Table 3. Suicidality Events by Country

Supplement Table 4. Restricted to the United States: Suicidality Events by Study

Supplement Table 5. Association Between Baseline Characteristics and Hazard of Suicidality (ITT Approach)*

Supplement Table 6. Restricted to the United States: Association Between Baseline Characteristics and Hazard of Suicidality (ITT DSMB)

Supplement Table 7. Restricted to the United States: Association Between Baseline Characteristics and Hazard of Suicidality (ITT Approach)

Supplement Table 8. Cause of Death Classifications (ITT)

Supplement Figure 1. Association between efavirenz and hazard of suicidality, according to baseline characteristics (ITT DSMB

primary approach).

Supplement Figure 2. Association between efavirenz and hazard of suicidality, according to baseline characteristics (ITT sensitivity

approach).

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Supplement Table 1. Baseline Characteristics by Study and Efavirenz Assignment

Characteristic

A5095 EFV

(N=765)

A5095 EFV-free (N=382)

A5142 EFV

(N=502)

A5142 EFV-free (N=255)

A5175 EFV

(N=1045)

A5175 EFV-free (N=526)

A5202 EFV

(N=929)

A5202 EFV-free (N=928)

Country Brazil -- -- -- -- 155 (15%) 76 (14%) -- -- Haiti -- -- -- -- 68 (7%) 32 (6%) -- -- India -- -- -- -- 169 (16%) 86 (16%) -- -- Malawi -- -- -- -- 147 (14%) 74 (14%) -- -- Peru -- -- -- -- 86 (8%) 48 (9%) -- -- South Africa -- -- 12 (2%) 8 (3%) 140 (13%) 70 (13%) -- -- Thailand -- -- -- -- 67 (6%) 33 (6%) -- -- United States 765 (100%) 382 (100%) 490 (98%) 247 (97%) 140 (13%) 70 (13%) 929 (100%) 928 (100%) Zimbabwe -- -- -- -- 73 (7%) 37 (7%) -- --

Sex Male 620 (81%) 309 (81%) 410 (82%) 195 (76%) 562 (54%) 270 (51%) 760 (82%) 775 (84%) Female 145 (19%) 73 (19%) 92 (18%) 60 (24%) 483 (46%) 256 (49%) 169 (18%) 153 (16%)

Race or ethnic group (United States)

N 765 382 490 247 140 70 929 928

White Non-Hispanic 313 (41%) 149 (39%) 187 (38%) 88 (36%) 39 (28%) 23 (33%) 371 (40%) 375 (40%) Black Non-Hispanic 271 (35%) 142 (37%) 186 (38%) 109 (44%) 59 (42%) 26 (37%) 315 (34%) 300 (32%) Hispanic 165 (22%) 83 (22%) 103 (21%) 45 (18%) 38 (27%) 18 (26%) 210 (23%) 219 (24%) Asian 10 (1%) 5 (1%) 11 (2%) 4 (2%) 1 (1%) 0 (0%) 13 (1%) 19 (2%) American Indian/Alaska

Native 3 (0%) 3 (1%) 2 (0%) 0 (0%) 0 (0%) 2 (3%) 9 (1%) 5 (1%)

Other 3 (0%) 0 (0%) 1 (0%) 1 (0%) 3 (2%) 1 (1%) 11 (1%) 10 (1%) Race or ethnic group (Multinational non-US)

N 0 0 12 8 905 456 0 0

White Non-Hispanic -- -- 0 (0%) 0 (0%) 55 (6%) 22 (5%) -- -- Black Non-Hispanic -- -- 12 (100%) 8 (100%) 442 (49%) 219 (48%) -- -- Hispanic -- -- 0 (0%) 0 (0%) 170 (19%) 96 (21%) -- -- Asian -- -- 0 (0%) 0 (0%) 238 (26%) 119 (26%) -- --

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Characteristic

A5095 EFV

(N=765)

A5095 EFV-free (N=382)

A5142 EFV

(N=502)

A5142 EFV-free (N=255)

A5175 EFV

(N=1045)

A5175 EFV-free (N=526)

A5202 EFV

(N=929)

A5202 EFV-free (N=928)

Age, years Median (Q1, Q3) 37 (31, 43) 37 (32, 43) 38 (32, 44) 37 (32, 44) 34 (29, 41) 34 (29, 41) 38 (31, 45) 38 (31, 45) <30 155 (20%) 61 (16%) 94 (19%) 42 (16%) 287 (27%) 146 (28%) 201 (22%) 203 (22%)

30-44 457 (60%) 243 (64%) 285 (57%) 156 (61%) 607 (58%) 310 (59%) 483 (52%) 474 (51%) ≥45 153 (20%) 78 (20%) 123 (25%) 57 (22%) 151 (14%) 70 (13%) 245 (26%) 251 (27%)

Pre-treatment CD4 count, x 109 cells/L

Median (Q1, Q3) 0.213 (0.077, 0.333)

0.197 (0.079, 0.344)

0.190 (0.043, 0.315)

0.189 (0.070, 0.300)

0.167 (0.089, 0.228)

0.183 (0.096, 0.235)

0.230 (0.103, 0.333)

0.227 (0.081, 0.335)

0-0.049 155 (20%) 65 (17%) 134 (27%) 49 (19%) 137 (13%) 63 (12%) 163 (18%) 176 (19%) 0.050-0.199 206 (27%) 126 (33%) 125 (25%) 89 (35%) 519 (50%) 238 (45%) 228 (25%) 233 (25%) 0.200-0.349 229 (30%) 103 (27%) 138 (28%) 81 (32%) 389 (37%) 225 (43%) 341 (37%) 315 (34%) >0.349 175 (23%) 87 (23%) 103 (21%) 36 (14%) 0 (0%) 0 (0%) 196 (21%) 204 (22%)

HIV-1 RNA, log10 copies/mL

Median (Q1, Q3) 4.77 (4.38, 5.41)

4.76 (4.40, 5.28)

4.81 (4.42, 5.25)

4.76 (4.47, 5.20)

5.02 (4.59, 5.44)

5.06 (4.55, 5.49)

4.67 (4.34, 4.95)

4.65 (4.31, 5.12)

< 100,000 464 (61%) 231 (60%) 314 (63%) 163 (64%) 509 (49%) 245 (47%) 714 (77%) 667 (72%) ≥ 100,000 301 (39%) 151 (40%) 188 (37%) 91 (36%) 536 (51%) 280 (53%) 215 (23%) 261 (28%)

History of AIDS None recorded 627 (82%) 303 (79%) 413 (82%) 209 (82%) 932 (89%) 472 (90%) 775 (83%) 778 (84%) Yes 138 (18%) 79 (21%) 89 (18%) 46 (18%) 113 (11%) 54 (10%) 154 (17%) 150 (16%)

Injection drug history None recorded 683 (89%) 341 (89%) 454 (90%) 227 (89%) 1,014 (97%) 516 (98%) 840 (90%) 857 (92%) Yes 82 (11%) 41 (11%) 48 (10%) 28 (11%) 31 (3%) 10 (2%) 89 (10%) 71 (8%)

Psychiatric history or psychoactive medication*

None recorded 521 (68%) 255 (67%) 339 (68%) 176 (69%) 880 (84%) 432 (82%) 492 (53%) 529 (57%) Yes 244 (32%) 127 (33%) 163 (32%) 79 (31%) 165 (16%) 94 (18%) 437 (47%) 399 (43%)

Psychoactive medication* None recorded 640 (84%) 320 (84%) 472 (94%) 247 (97%) 996 (95%) 495 (94%) 711 (77%) 744 (80%) Yes 125 (16%) 62 (16%) 30 (6%) 8 (3%) 49 (5%) 31 (6%) 218 (23%) 184 (20%)

Depression-related history or antidepressant medication*

None recorded 618 (81%) 297 (78%) 405 (81%) 214 (84%) 958 (92%) 472 (90%) 638 (69%) 653 (70%) Yes 147 (19%) 85 (22%) 97 (19%) 41 (16%) 87 (8%) 54 (10%) 291 (31%) 275 (30%)

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Characteristic

A5095 EFV

(N=765)

A5095 EFV-free (N=382)

A5142 EFV

(N=502)

A5142 EFV-free (N=255)

A5175 EFV

(N=1045)

A5175 EFV-free (N=526)

A5202 EFV

(N=929)

A5202 EFV-free (N=928)

Antidepressant medication*

None recorded 670 (88%) 335 (88%) 476 (95%) 250 (98%) 1,006 (96%) 505 (96%) 764 (82%) 783 (84%) Yes 95 (12%) 47 (12%) 26 (5%) 5 (2%) 39 (4%) 21 (4%) 165 (18%) 145 (16%)

Body mass index, kg/m2 Median (Q1, Q3) 24.3 (21.8, 27.6)

24.8 (21.9, 27.5)

24.8 (22.0, 27.8)

24.5 (21.9, 28.1)

22.4 (20.2, 25.2)

22.2 (20.1, 24.8)

24.8 (22.2, 27.9)

24.8 (22.1, 28.1)

Underweight (< 18.5) 29 (4%) 16 (4%) 21 (4%) 9 (4%) 91 (9%) 61 (12%) 37 (4%) 33 (4%) Normal (<25) 377 (52%) 181 (48%) 241 (49%) 127 (51%) 680 (65%) 343 (65%) 438 (47%) 448 (48%) Overweight (<30) 221 (30%) 131 (35%) 155 (31%) 72 (29%) 201 (19%) 87 (17%) 317 (34%) 301 (32%) Obese (30+) 104 (14%) 47 (13%) 79 (16%) 43 (17%) 73 (7%) 35 (7%) 136 (15%) 146 (16%)

Baseline weight, kg Median (Q1, Q3) 74 (65, 84) 75 (65, 84) 74 (64, 86) 73 (65, 83) 61 (54, 70) 60 (53, 69) 75 (66, 86) 75 (66, 86) <60 112 (15%) 56 (15%) 85 (17%) 37 (15%) 490 (47%) 264 (50%) 123 (13%) 100 (11%)

60-<80 391 (51%) 191 (50%) 240 (48%) 135 (53%) 443 (42%) 208 (40%) 469 (50%) 483 (52%) ≥80 258 (34%) 132 (35%) 174 (35%) 82 (32%) 112 (11%) 54 (10%) 337 (36%) 345 (37%)

EFV=efavirenz. *Prescription psychoactive (or antidepressant) medication ongoing within 30 days before study entry.

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Supplement Table 2. Baseline Psychoactive Medications by Efavirenz Assignment* Generic name (Trade name) Efavirenz (n=3241) Efavirenz-free (n=2091)

Psychoactive Drug Category No. of participants on medication prestudy 422 (13%) 285 (14%) Antidepressant No. of participants on medication prestudy 325 (10%) 217 (10%)

Bupropion (Wellbutrin, Zyban) 59 (2%) 42 (2%) Trazodone (Desyrel) 54 (2%) 42 (2%) Sertraline (Zoloft) 46 (1%) 28 (1%) Amitriptyline (Amitrip, Elavil, Endep, Enovil, Trepiline,

Tryptanol) 40 (1%) 23 (1%)

Citalopram (Celexa) 38 (1%) 23 (1%) Paroxetine (Paxil) 40 (1%) 20 (1%) Escitalopram (Lexapro) 28 (1%) 25 (1%) Fluoxetine (Prozac, Sarafem) 27 (1%) 18 (1%) Venlafaxine (Effexor) 21 (1%) 20 (1%) Mirtazapine (Remeron) 14 (<0.5%) 12 (1%) Doxepin (Adapin, Sinequan) 4 (<0.5%) 7 (<0.5%) Nortriptyline (Aventyl, Pamelor) 6 (<0.5%) 2 (<0.5%) Duloxetine (Cymbalta) 4 (<0.5%) 2 (<0.5%) Imipramine (Janimine, Tofranil) 1 (0%) 2 (<0.5%) Desipramine (Norpramin, Pertofrane) 1 (0%) 0 (0%)

Anti-Anxiety No. of participants on medication prestudy 106 (3%) 77 (4%) Alprazolam (Niravam, Xanax) 36 (1%) 30 (1%) Lorazepam (Ativan, Tavor, Temesta) 29 (1%) 24 (1%) Clonazepam (Clonopin, Klonopin, Rivotril) 25 (1%) 13 (1%) Diazepam (Diastat, Valium, Valrelease, Zetran) 12 (<0.5%) 6 (<0.5%) Buspirone (BuSpar) 10 (<0.5%) 4 (<0.5%) Clorazepate Dipotassium (ClorazeCaps, ClorazeTabs,

GenENE, Tranxene) 1 (0%) 2 (<0.5%)

Chlordiazepoxide (Librium) 0 (0%) 1 (0%) Mood Stabilizing No. of participants on medication prestudy 83 (3%) 42 (2%)

Gabapentin (Neurontin) 39 (1%) 24 (1%) Divalproex Sodium (Depakote) 19 (1%) 9 (<0.5%) Lamotrigine (Lamictal) 11 (<0.5%) 7 (<0.5%) Carbamazepine (Atretol, Epitol, Tegretol) 9 (<0.5%) 3 (<0.5%) Oxcarbazepine (Trileptal) 4 (<0.5%) 1 (0%) Lithium Carbonate (Eskalith, Lithane, Lithobid, Lithotabs) 3 (<0.5%) 1 (0%) Topiramate (Topamax) 3 (<0.5%) 0 (0%) Valproate Sodium (Depakene Syrup, DPA sodium) 1 (0%) 0 (0%) Lithium Citrate (Cibalith-S Syrup, Eskalith Lithobid) 1 (0%) 0 (0%)

Antipsychotic No. of participants on medication pre-study 42 (1%) 35 (2%) Quetiapine (Seroquel) 14 (<0.5%) 15 (1%) Olanzapine (Zyprexa) 11 (<0.5%) 8 (<0.5%) Risperidone (Risperdal) 8 (<0.5%) 7 (<0.5%) Ziprasidone (Geodon) 4 (<0.5%) 2 (<0.5%) Aripiprazole (Abilify) 1 (0%) 4 (<0.5%)

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Generic name (Trade name) Efavirenz (n=3241) Efavirenz-free (n=2091) Chlorpromazine (Ormazine, Thorazine) 1 (0%) 1 (0%) Haloperidol (Haldol) 1 (0%) 1 (0%) Amitriptyline & Perphenazine (Etrafon, Triavil) 2 (<0.5%) 0 (0%) Fluphenazine (Permitil, Prolixin) 1 (0%) 1 (0%) Haloperidol Decanoate (Haldol Decanoate) 0 (0%) 1 (0%) Fluphenazine Decanoate (Prolixin Decanoate) 1 (0%) 0 (0%) Trifluoperazine (Stelazine) 1 (0%) 0 (0%) Thioridazine (Mellaril) 0 (0%) 1 (0%)

Attention deficit hyperactivity disorder (ADHD) No. of participants on medication prestudy 7 (<0.5%) 10 (1%)

Methylphenidate (Concerta, Metadate (CD/ER), Methylin, Ritalin (SR/LA))

4 (<0.5%) 5 (<0.5%)

Amphetamine Salts (Adderall (XR)) 1 (0%) 4 (<0.5%) Atomoxetine (Strattera) 2 (<0.5%) 1 (0%)

Antipsychotic & Antidepressant No. of participants on medication prestudy 0 (0%) 1 (0%)

Amitriptyline & Chlordiazepoxide (Limbitrol (DS)) 0 (0%) 1 (0%) * Prescription medication ongoing within 30 days before study entry; prescribing indication was not collected

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Supplement Table 3. Suicidality Events by Country

A. Intention-to-Treat Data Safety Monitoring Board Approach Efavirenz-containing Efavirenz-free

Country n Events PYs IR (95% CI)* n Events PYs IR (95% CI)* Total n United States 2324 39 4345.9 8.97 (6.38, 12.27) 1627 13 3353.6 3.88 (2.06, 6.63) 3951 India 169 2 261.6 7.65 (0.93, 27.62) 86 0 131.8 0.00 (0.00, 27.98) 255 Brazil 155 0 224.6 0.00 (0.00, 16.42) 76 1 108.6 9.21 (0.23, 51.29) 231 South Africa 152 1 258.5 3.87 (0.10, 21.55) 78 0 134.4 0.00 (0.00, 27.45) 230 Malawi 147 0 250.7 0.00 (0.00, 14.71) 74 0 124.9 0.00 (0.00, 29.52) 221 Peru 86 1 142.8 7.00 (0.18, 39.00) 48 1 76.5 13.07 (0.33, 72.82) 134 Zimbabwe 73 0 127.5 0.00 (0.00, 28.92) 37 0 65.7 0.00 (0.00, 56.12) 110 Haiti 68 0 104.8 0.00 (0.00, 35.19) 32 0 51.6 0.00 (0.00, 71.50) 100 Thailand 67 4 100.6 39.78 (10.84, 101.85) 33 0 51.3 0.00 (0.00, 71.88) 100

B. Intention-to-Treat Approach Efavirenz-containing Efavirenz-free

Country n Events PYs IR (95% CI)* n Events PYs IR (95% CI)* Total n United States 2324 48 5736.2 8.37 (6.17, 11.09) 1627 15 4040.0 3.71 (2.08, 6.12) 3951 India 169 5 568.0 8.80 (2.86, 20.54) 86 2 286.8 6.97 (0.84, 25.19) 255 Brazil 155 1 512.9 1.95 (0.05, 10.86) 76 1 251.9 3.97 (0.10, 22.12) 231 South Africa 152 1 503.7 1.99 (0.05, 11.06) 78 1 256.2 3.90 (0.10, 21.75) 230 Malawi 147 0 479.3 0.00 (0.00, 7.70) 74 0 236.3 0.00 (0.00, 15.61) 221 Peru 86 4 293.6 13.63 (3.71, 34.89) 48 1 160.4 6.23 (0.16, 34.73) 134 Zimbabwe 73 0 258.0 0.00 (0.00, 14.30) 37 0 130.0 0.00 (0.00, 28.38) 110 Haiti 68 0 223.2 0.00 (0.00, 16.52) 32 0 112.1 0.00 (0.00, 32.91) 100 Thailand 67 4 212.5 18.82 (5.13, 48.20) 33 0 112.1 0.00 (0.00, 32.90) 100

IR=incidence rate per 1000 PYs. PYs=person-years. Countries are ordered by sample size. *Exact Poisson 95% confidence interval for crude incidence rate per 1000 PYs

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Supplement Table 4. Restricted to the United States: Suicidality Events by Study

A. Intention-to-Treat Data Safety Monitoring Board Approach Efavirenz-containing Efavirenz-free

Study n Events PYs IR (95% CI)* n Events PYs IR (95% CI)* A5095 765 6 738.6 8.12 (2.98, 17.68) 382 1 364.2 2.75 (0.07, 15.30) A5142 490 8 981.4 8.15 (3.52, 16.06) 247 2 496.0 4.03 (0.49, 14.56) A5175 140 5 311.0 16.08 (5.22, 37.52) 70 0 157.7 0.00 (0.00, 23.39) A5202 929 20 2314.9 8.64 (5.28, 13.34) 928 10 2335.6 4.28 (2.05, 7.87)

B. Intention-to-Treat Approach Efavirenz-containing Efavirenz-free

Study n Events PYs IR (95% CI)* n Events PYs IR (95% CI)* A5095 765 14 1983.6 7.06 (3.86, 11.84) 382 2 969.5 2.06 (0.25, 7.45) A5142 490 8 981.4 8.15 (3.52, 16.06) 247 2 496.0 4.03 (0.49, 14.56) A5175 140 6 456.4 13.15 (4.82, 28.62) 70 1 238.8 4.19 (0.11, 23.33) A5202 929 20 2314.9 8.64 (5.28, 13.34) 928 10 2335.6 4.28 (2.05, 7.87)

IR=incidence rate per 1000 PYs. PYs=person-years. *Exact Poisson 95% confidence interval for crude incidence rate per 1000 PYs

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Supplement Table 5. Association Between Baseline Characteristics and Hazard of Suicidality (ITT Approach)*

Univariate Models Multivariable model† (n=5318, 83 events)

Characteristic DF n HR (95% CI) P-

value HR (95% CI) P-value Randomly assigned treatment group

Efavirenz-containing vs. Efavirenz-free 1 5332 2.10 (1.26, 3.49) 0.004 1.94 (1.17, 3.23) 0.011

Sex Female vs. Male 1 5332 0.85 (0.51, 1.43) 0.55 0.79 (0.46, 1.37) 0.41 Race or ethnic group, United States only

White vs. Black 2 3834 1.60 (0.91, 2.81) 0.064 . Hispanic vs. Black 0.74 (0.33, 1.63)

Age categories <30 vs. ≥45 years 2 5332 2.96 (1.44, 6.08) 0.005 3.58 (1.71, 7.48) 0.001 30-44 vs. ≥45 years 1.64 (0.82, 3.27) 1.81 (0.90, 3.63)

CD4 count categories 0-0.049 vs. >0.349 x109 cells/L 3 5328 0.43 (0.19, 0.98) 0.033 0.44 (0.18, 1.09) 0.143 0.050-0.199 vs. >0.349 x109 cells/L 0.47 (0.24, 0.94) 0.55 (0.27, 1.15) 0.200-0.349 vs. >0.349 x109 cells/L 0.87 (0.47, 1.60) 0.90 (0.49, 1.67)

HIV-1 RNA categories ≥100,000 vs. <100,000 copies/mL 1 5330 0.73 (0.45, 1.17) 0.190 0.85 (0.51, 1.42) 0.53 History of AIDS Yes vs. No 1 5332 0.93 (0.50, 1.72) 0.81 1.33 (0.68, 2.62) 0.40 Injection drug history Yes vs. No 1 5332 3.23 (1.82, 5.72) <0.001 2.70 (1.50, 4.88) <0.001 Psychiatric history or psychoactive Rx

Yes vs. No 1 5332 3.72 (2.35, 5.88) <0.001 3.75 (2.33, 6.03) <0.001

BMI categories Underweight (< 18.5) vs. Normal (<25) 3 5280 1.38 (0.62, 3.05) 0.29 . Overweight (<30) vs. Normal (<25) 0.68 (0.39, 1.17) Obese (30+) vs. Normal (<25) 0.68 (0.32, 1.43)

Weight categories <60 vs. ≥80 kg 2 5321 1.24 (0.67, 2.29) 0.39 1.48 (0.77, 2.86) 0.158 60-<80 vs. ≥80 kg 0.85 (0.50, 1.44) 0.84 (0.49, 1.44)

BMI=body mass index. DF=degrees of freedom. HR=hazard ratio. ITT=intention-to-treat. *All on-study follow-up was included (ITT approach); Cox model Wald CI and p-values are presented, each model was stratified by study. †In multivariable analysis, race or ethnic group was omitted because analysis of this covariate was restricted to the United States, and BMI category was omitted due to collinearity with body weight and missing height observations; otherwise covariates were included in this multivariable model.

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Supplement Table 6. Restricted to the United States: Association Between Baseline Characteristics and Hazard of Suicidality (ITT DSMB)*

Univariate Models Multivariable model† (n=3821, 51 events)

Characteristic DF n HR (95% CI) P-value HR (95% CI) P-

value Randomly assigned treatment group

Efavirenz-containing vs. Efavirenz-free 1 3951 2.32 (1.23, 4.38) 0.009 2.02 (1.06, 3.82) 0.031

Sex Female vs. Male 1 3951 0.71 (0.32, 1.57) 0.39 0.61 (0.26, 1.43) 0.26 Race or ethnic group

White vs. Black 2 3834 1.67 (0.89, 3.12) 0.107 1.23 (0.63, 2.41) 0.47 Hispanic vs. Black 0.81 (0.34, 1.92) 0.75 (0.31, 1.79)

Age categories <30 vs. ≥45 years 2 3951 1.78 (0.76, 4.16) 0.39 2.12 (0.88, 5.08) 0.24 30-44 vs. ≥45 years 1.54 (0.73, 3.25) 1.66 (0.78, 3.54)

CD4 count categories 0-0.049 vs. >0.349 x109 cells/L 3 3947 0.34 (0.12, 0.95) 0.114 0.27 (0.08, 0.87) 0.111 0.050-0.199 vs. >0.349 x109 cells/L 0.54 (0.24, 1.21) 0.49 (0.20, 1.18) 0.200-0.349 vs. >0.349 x109 cells/L 0.88 (0.44, 1.74) 0.85 (0.42, 1.69)

HIV-1 RNA categories ≥100,000 vs. <100,000 copies/mL 1 3950 0.95 (0.52, 1.73) 0.87 0.98 (0.50, 1.93) 0.95 History of AIDS Yes vs. No 1 3951 1.13 (0.57, 2.25) 0.73 1.70 (0.75, 3.88) 0.20 Injection drug history Yes vs. No 1 3951 2.81 (1.44, 5.47) 0.002 2.30 (1.16, 4.59) 0.018 Psychiatric history or psychoactive Rx

Yes vs. No 1 3951 4.22 (2.28, 7.82) <0.001 3.51 (1.85, 6.64) <0.001

BMI categories Underweight (< 18.5) vs. Normal (<25) 3 3899 1.74 (0.61, 4.94) 0.177 . Overweight (<30) vs. Normal (<25) 0.64 (0.33, 1.22) Obese (30+) vs. Normal (<25) 0.53 (0.21, 1.38)

Weight categories <60 vs. ≥80 kg 2 3940 2.02 (0.93, 4.40) 0.20 2.70 (1.14, 6.41) 0.072 60-<80 vs. ≥80 kg 1.23 (0.65, 2.33) 1.28 (0.67, 2.45)

BMI=body mass index. DF=degrees of freedom. DSMB=data safety monitoring board. HR=hazard ratio. ITT=intention-to-treat. *Cox model Wald CI and p-values are presented, each model was stratified by study. †Multivariable analysis was restricted to participants of white, black, or Hispanic race or ethnic group with complete covariate information; BMI was omitted due to collinearity with body weight and missing height observations.

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Supplement Table 7. Restricted to the United States: Association Between Baseline Characteristics and Hazard of Suicidality (ITT Approach)*

Univariate Models Multivariable model† (n=3821, 62 events)

Characteristic DF n HR (95% CI) P-value HR (95% CI) P-value Randomly assigned treatment group

Efavirenz-containing vs. Efavirenz-free

1 3951 2.31 (1.29, 4.16) 0.005 2.06 (1.14, 3.71) 0.017

Sex Female vs. Male 1 3951 0.75 (0.37, 1.51) 0.42 0.73 (0.34, 1.55) 0.41 Race or ethnic group

White vs. Black 2 3834 1.60 (0.91, 2.81) 0.064 1.25 (0.69, 2.27) 0.35 Hispanic vs. Black 0.74 (0.33, 1.63) 0.72 (0.32, 1.62)

Age categories <30 vs. ≥45 years 2 3951 2.33 (1.04, 5.23) 0.120 3.01 (1.31, 6.91) 0.035 30-44 vs. ≥45 years 1.83 (0.88, 3.79) 2.00 (0.95, 4.18)

CD4 count categories 0-0.049 vs. >0.349 x109 cells/L 3 3947 0.45 (0.19, 1.05) 0.141 0.52 (0.20, 1.39) 0.46 0.050-0.199 vs. >0.349 x109 cells/L 0.51 (0.25, 1.07) 0.58 (0.26, 1.27) 0.200-0.349 vs. >0.349 x109 cells/L 0.83 (0.44, 1.55) 0.83 (0.44, 1.57)

HIV-1 RNA categories ≥100,000 vs. <100,000 copies/mL 1 3950 0.79 (0.45, 1.38) 0.41 0.80 (0.43, 1.49) 0.48 History of AIDS Yes vs. No 1 3951 0.87 (0.44, 1.71) 0.69 1.21 (0.54, 2.72) 0.65 Injection drug history Yes vs. No 1 3951 3.29 (1.84, 5.89) <0.001 2.81 (1.53, 5.14) <0.001 Psychiatric history or psychoactive Rx

Yes vs. No 1 3951 4.14 (2.39, 7.19) <0.001 3.47 (1.96, 6.13) <0.001

BMI categories Underweight (< 18.5) vs. Normal (<25)

3 3899 1.41 (0.50, 3.97) 0.21 .

Overweight (<30) vs. Normal (<25) 0.64 (0.36, 1.16) Obese (30+) vs. Normal (<25) 0.53 (0.22, 1.26)

Weight categories <60 vs. ≥80 kg 2 3940 1.35 (0.65, 2.79) 0.62 1.72 (0.77, 3.86) 0.33 60-<80 vs. ≥80 kg 0.97 (0.56, 1.68) 0.99 (0.56, 1.73)

BMI=body mass index. DF=degrees of freedom. HR=hazard ratio. ITT=intention-to-treat. *Cox model Wald CI and p-values are presented, each model was stratified by study. †Multivariable analysis was restricted to participants of white, black, or Hispanic race or ethnic group with complete covariate information; BMI was omitted due to collinearity with body weight and missing height observations.

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Supplement Table 8. Cause of Death Classifications (ITT)

United States* Multinational† All Participants (Total)

Efavirenz Efavirenz-free Efavirenz Efavirenz-free Efavirenz Efavirenz-free n=2324 n=1627 n=917 n=464 n=3241 n=2091

5798.86 PY 4056.76 PY 3074.83 PY 1552.82 PY 8873.68 PY 5609.57 PY Cause of death

Freq (%) Incidence

Freq (%) Incidence

Freq (%) Incidence

Freq (%) Incidence

Freq (%) Incidence

Freq (%) Incidence

Suicide 6 (0.26) 1.03 1

(0.06) 0.25 2 (0.22) 0.65 0 0 8

(0.25) 0.90 1 (0.05) 0.18

Substance Abuse

3 (0.13) 0.52 2

(0.12) 0.49 0 0 0 0 3 (0.09) 0.34 2

(0.10) 0.36

Homicide 0 0 0 0 2 (0.22) 0.65 0 0 2

(0.06) 0.23 0 0

Accident 5 (0.22) 0.86 3

(0.18) 0.74 2 (0.22) 0.65 0 0 7

(0.22) 0.79 3 (0.14) 0.53

Unknown 3 (0.13) 0.52 1

(0.06) 0.25 5 (0.55) 1.63 0 0 8

(0.25) 0.90 1 (0.05) 0.18

Other cause‡

30 (1.29) 5.17 21

(1.29) 5.18 26 (2.84) 8.46 15

(3.23) 9.66 56 (1.73) 6.31 36

(1.72) 6.42

All causes, total

47 (2.02) 8.11 28

(1.72) 6.90 37 (4.03) 12.03 15

(3.23) 9.66 84 (2.59) 9.47 43

(2.06) 7.67

ITT= intention-to-treat. PY=person-years. Incidence is presented per 1000 PY. Death frequency and incidence are summarized using the intention-to-treat approach to account for all deaths reported during study follow-up. *United States: Suicide method: gunshot (n=3), hanging (1), overdose (n=2: 1 efavirenz, 1 efavirenz-free), method not reported (1). Substance abuse: substance not reported (2), cocaine (1), heroin (1), amphetamine (1). Accident type: motor vehicle (n=6: 4 efavirenz, 2 efavirenz-free), asphyxia (1 efavirenz-free), fire (1 efavirenz). †Multinational (n): Brazil (231), Haiti (100), India (255), Malawi (221), Peru (134), South Africa (230), Thailand (100), Zimbabwe (110). Suicide method: hanging (1), method not reported (1). Homicide: assassinated by gunshot (1), stabbed during a street quarrel (1). Accident type: motor vehicle (1), earthquake (1). ‡ Other cause: e.g., infection, cancer, organ failure.

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Supplement Figure 1. Association between efavirenz and hazard of suicidality, according to baseline characteristics (ITT DSMB primary approach). DSMB=data safety monitoring board. IR=crude incidence rate. ITT=intention-to-treat. PY=person-years. Rx=medication. Univariate estimated hazard ratios were quantified from a Cox model with a Wald CI and p-value, stratified by study, and are plotted on a logarithm scale. The continuous age variable presents the efavirenz association when age is held fixed at 25, 35, and 45 years old. *The first p-value tests the main effect of efavirenz; subsequent p-values test for an interaction between efavirenz and the baseline characteristic. †Race or ethnic group was limited to white, black and Hispanic participants enrolled in the United States.

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Supplement Figure 2. Association between efavirenz and hazard of suicidality, according to baseline characteristics (ITT sensitivity approach). IR=crude incidence rate. ITT=intention-to-treat. PY=person-years. Rx=medication. Univariate estimated hazard ratios were quantified from a Cox model with a Wald CI and p-value, stratified by study, and are plotted on a logarithm scale. The continuous age variable presents the efavirenz association when age is held fixed at 25, 35, and 45 years old. *The first p-value tests the main effect of efavirenz; subsequent p-values test for an interaction between efavirenz and the baseline characteristic. †Race or ethnic group was limited to white, black and Hispanic participants enrolled in the United States.

Downloaded From: http://annals.org/ by Jules Levin on 06/30/2014