Risk of inhibitor development according to treatment characteristic
| . | All inhibitors . | High-titer inhibitors* . | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| . | Proportion of Inh (%) . | Crude RR (CI) . | P for trend . | Adjusted RR (CI) . | P for trend . | Proportion of Inh (%) . | Crude RR (CI) . | P for trend . | Adjusted RR (CI) . | P for trend . |
| At first factor VIII exposure | ||||||||||
| Age at first exposure | ||||||||||
| More than 18 mo | 10/57 (18) | 1.0 | .005 | 1.0§ | .21 | 9/57 (16) | 1.0 | .02 | 1.0§ | .63 |
| 12 to 18 mo | 16/82 (20) | 1.1 (0.5-2.5) | 1.2 (0.5-2.9) | 13/82 (16) | 1.0 (0.4-2.4) | 1.0 (0.4-2.6) | ||||
| 6 to 12 mo | 30/130 (23) | 1.3 (0.7-2.7) | 1.5 (0.6-3.4) | 23/130 (18) | 1.1 (0.5-2.5) | 1.1 (0.4-2.6) | ||||
| 1 to 6 mo | 13/43 (30) | 1.9 (0.8-4.3) | 1.8 (0.7-4.7) | 10/43 (23) | 1.6 (0.6-3.9) | 1.3 (0.5-3.8) | ||||
| Less than 1 mo | 16/39 (41) | 2.7 (1.2-5.9) | 1.6 (0.6-4.1) | 13/39 (33) | 2.4 (1.0-5.6) | 1.1 (0.4-3.2) | ||||
| Reason for first factor VIII treatment | ||||||||||
| Bleed | 65/286 (23) | 1.0 | 1.0‖ | 50/286 (17) | 1.0 | 1.0‖ | ||||
| Prophylaxis | 8/37 (22) | 1.0 (0.5-2.0) | .92 | 1.0 (0.5-2.2) | .95 | 7/37 (19) | 1.1 (0.5-2.4) | .82 | 1.2 (0.5-2.8) | .63 |
| Surgical procedure | 11/17 (65) | 3.7 (2.0-7.1) | < .001 | 2.6 (1.3-5.1) | .007 | 10/17 (59) | 4.4 (2.2-8.7) | < .001 | 3.2 (1.6-6.7) | .002 |
| Peak treatment moment at first treatment episode† | ||||||||||
| None | 44/229 (19) | 1.0 | 1.0¶ | 31/229 (14) | 1.0 | 1.0¶ | ||||
| 3 to 4 days | 7/36 (19) | 1.0 (0.5-2.3) | .98 | 1.1 (0.5-2.4) | .87 | 6/36 (17) | 1.2 (0.5-2.9) | .66 | 1.3 (0.5-3.1) | .63 |
| At least 5 days | 32/57 (56) | 3.3 (2.1-5.3) | < .001 | 3.1 (1.9-5.0) | < .001 | 30/57 (53) | 4.3 (2.6-7.1) | < .001 | 4.1 (2.4-7.0) | < .001 |
| During first 50 exposure days | ||||||||||
| After peak treatment moment compared with before | NA | 1.6 (1.0-2.7) | .06 | 1.5 (0.9-2.5)¶ | .14 | NA | 1.7 (1.0-2.9) | .07 | 1.5 (0.8-2.6)¶ | .18 |
| After major peak treatment moment compared with before | NA | 2.0 (1.3-3.1) | .002 | 1.6 (1.0-2.6)¶ | .03 | NA | 2.3 (1.4-3.7) | .001 | 1.9 (1.1-3.1)¶ | .02 |
| After major surgical procedure compared with before | NA | 1.4 (0.8-2.5) | .21 | 1.3 (0.8-2.3)¶ | .32 | NA | 1.3 (0.7-2.5) | .43 | 1.2 (0.6-2.3)¶ | .61 |
| Duration between exposure days‡ | ||||||||||
| More than 50 d | NA | 1.0 | .03 | 1.0# | .26 | NA | 1.0 | .06 | 1.0# | .62 |
| 10 to 50 d | NA | 0.8 (0.4-1.6) | 0.8 (0.4-1.6) | NA | 0.6 (0.3-1.4) | 0.6 (0.3-1.4) | ||||
| Fewer than 10 d | NA | 1.9 (1.1-3.3) | 1.5 (0.8-2.7) | NA | 1.9 (1.1-3.4) | 1.3 (0.7-2.5) | ||||
| Dose of factor VIII product‡ | ||||||||||
| Less than 35 IU/kg | NA | 1.0 | < .001 | 1.0** | .01 | NA | 1.0 | < .001 | 1.0** | .01 |
| 35 to 50 IU/kg | NA | 1.4 (0.7-3.0) | 1.2 (0.6-2.6) | NA | 1.7 (0.7-4.0) | 1.5 (0.6-3.6) | ||||
| More than 50 IU/kg | NA | 3.3 (1.7-6.5) | 2.3 (1.2-4.7) | NA | 4.2 (1.9-9.3) | 3.0 (1.3-6.9) | ||||
| Regular prophylaxis | NA | 0.4 (0.2-0.8) | .01 | 0.5 (0.2-0.9)†† | .02 | NA | 0.5 (0.2-0.9) | .03 | 0.5 (0.2-1.0)†† | .05 |
| . | All inhibitors . | High-titer inhibitors* . | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| . | Proportion of Inh (%) . | Crude RR (CI) . | P for trend . | Adjusted RR (CI) . | P for trend . | Proportion of Inh (%) . | Crude RR (CI) . | P for trend . | Adjusted RR (CI) . | P for trend . |
| At first factor VIII exposure | ||||||||||
| Age at first exposure | ||||||||||
| More than 18 mo | 10/57 (18) | 1.0 | .005 | 1.0§ | .21 | 9/57 (16) | 1.0 | .02 | 1.0§ | .63 |
| 12 to 18 mo | 16/82 (20) | 1.1 (0.5-2.5) | 1.2 (0.5-2.9) | 13/82 (16) | 1.0 (0.4-2.4) | 1.0 (0.4-2.6) | ||||
| 6 to 12 mo | 30/130 (23) | 1.3 (0.7-2.7) | 1.5 (0.6-3.4) | 23/130 (18) | 1.1 (0.5-2.5) | 1.1 (0.4-2.6) | ||||
| 1 to 6 mo | 13/43 (30) | 1.9 (0.8-4.3) | 1.8 (0.7-4.7) | 10/43 (23) | 1.6 (0.6-3.9) | 1.3 (0.5-3.8) | ||||
| Less than 1 mo | 16/39 (41) | 2.7 (1.2-5.9) | 1.6 (0.6-4.1) | 13/39 (33) | 2.4 (1.0-5.6) | 1.1 (0.4-3.2) | ||||
| Reason for first factor VIII treatment | ||||||||||
| Bleed | 65/286 (23) | 1.0 | 1.0‖ | 50/286 (17) | 1.0 | 1.0‖ | ||||
| Prophylaxis | 8/37 (22) | 1.0 (0.5-2.0) | .92 | 1.0 (0.5-2.2) | .95 | 7/37 (19) | 1.1 (0.5-2.4) | .82 | 1.2 (0.5-2.8) | .63 |
| Surgical procedure | 11/17 (65) | 3.7 (2.0-7.1) | < .001 | 2.6 (1.3-5.1) | .007 | 10/17 (59) | 4.4 (2.2-8.7) | < .001 | 3.2 (1.6-6.7) | .002 |
| Peak treatment moment at first treatment episode† | ||||||||||
| None | 44/229 (19) | 1.0 | 1.0¶ | 31/229 (14) | 1.0 | 1.0¶ | ||||
| 3 to 4 days | 7/36 (19) | 1.0 (0.5-2.3) | .98 | 1.1 (0.5-2.4) | .87 | 6/36 (17) | 1.2 (0.5-2.9) | .66 | 1.3 (0.5-3.1) | .63 |
| At least 5 days | 32/57 (56) | 3.3 (2.1-5.3) | < .001 | 3.1 (1.9-5.0) | < .001 | 30/57 (53) | 4.3 (2.6-7.1) | < .001 | 4.1 (2.4-7.0) | < .001 |
| During first 50 exposure days | ||||||||||
| After peak treatment moment compared with before | NA | 1.6 (1.0-2.7) | .06 | 1.5 (0.9-2.5)¶ | .14 | NA | 1.7 (1.0-2.9) | .07 | 1.5 (0.8-2.6)¶ | .18 |
| After major peak treatment moment compared with before | NA | 2.0 (1.3-3.1) | .002 | 1.6 (1.0-2.6)¶ | .03 | NA | 2.3 (1.4-3.7) | .001 | 1.9 (1.1-3.1)¶ | .02 |
| After major surgical procedure compared with before | NA | 1.4 (0.8-2.5) | .21 | 1.3 (0.8-2.3)¶ | .32 | NA | 1.3 (0.7-2.5) | .43 | 1.2 (0.6-2.3)¶ | .61 |
| Duration between exposure days‡ | ||||||||||
| More than 50 d | NA | 1.0 | .03 | 1.0# | .26 | NA | 1.0 | .06 | 1.0# | .62 |
| 10 to 50 d | NA | 0.8 (0.4-1.6) | 0.8 (0.4-1.6) | NA | 0.6 (0.3-1.4) | 0.6 (0.3-1.4) | ||||
| Fewer than 10 d | NA | 1.9 (1.1-3.3) | 1.5 (0.8-2.7) | NA | 1.9 (1.1-3.4) | 1.3 (0.7-2.5) | ||||
| Dose of factor VIII product‡ | ||||||||||
| Less than 35 IU/kg | NA | 1.0 | < .001 | 1.0** | .01 | NA | 1.0 | < .001 | 1.0** | .01 |
| 35 to 50 IU/kg | NA | 1.4 (0.7-3.0) | 1.2 (0.6-2.6) | NA | 1.7 (0.7-4.0) | 1.5 (0.6-3.6) | ||||
| More than 50 IU/kg | NA | 3.3 (1.7-6.5) | 2.3 (1.2-4.7) | NA | 4.2 (1.9-9.3) | 3.0 (1.3-6.9) | ||||
| Regular prophylaxis | NA | 0.4 (0.2-0.8) | .01 | 0.5 (0.2-0.9)†† | .02 | NA | 0.5 (0.2-0.9) | .03 | 0.5 (0.2-1.0)†† | .05 |
Inh indicates inhibitors; NA, not applicable.
*High-titer inhibitor was defined as a clinically relevant inhibitor with inhibitor titers of at least 5 Bethesda units/mL at any time.
†Only 2 of the 7 patients who developed inhibitors before the fifth exposure day received treatment with factor VIII on consecutive days (2); the others received treatment on single days before inhibitor development.
‡In patients who were treated on demand during the first 50 exposure days.
§Adjusted for baseline factor VIII activity level, ethnicity, factor VIII gene mutation type, duration between exposure days, dose, prophylaxis, peak treatment moment at first treatment, reason of first treatment, and product type.
∥Adjusted for baseline factor VIII activity level, ethnicity, factor VIII gene mutation type, age at first exposure, duration between exposure days, dose, prophylaxis, and product type.
¶Adjusted for baseline factor VIII activity level, ethnicity, factor VIII gene mutation type, age at first exposure, prophylaxis, and product type.
#Adjusted for baseline factor VIII activity level, ethnicity, factor VIII gene mutation type, age at first exposure, dose, prophylaxis, and product type.
**Adjusted for baseline factor VIII activity level, ethnicity, factor VIII gene mutation type, age at first exposure, duration between [AU12] exposure days, prophylaxis, product type, and body weight.
††Adjusted for baseline factor VIII activity level, ethnicity, factor VIII gene mutation type, age at first exposure, duration between exposure days, dose, and product type.