Key points
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The combination of sofosbuvir and simeprevir results in an overall SVR12 of 92.6, 90% in patients with genotype 1a infection, 94.2% with genotype 1b and 91.6% with genotype 4.
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The safety of the sofosbuvir and simeprevir combination was acceptable with only 3% of early discontinuations and with no new safety warnings.
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The combination with sofosbuvir and simeprevir is no longer recommended but remains a potential therapeutic option in resource-limited settings or in countries where simeprevir is still available.
Background
Methods
Study design and participants
Outcomes
Statistical analyses
Role of the funding source
Results
Patient population
SOF SMV 12 weeks n = 485 | SOF SMV 24 weeks n = 51 | SOF SMV RBV 12 weeks n = 45 | SOF SMV RBV 24 weeks n = 18 | p value | |
---|---|---|---|---|---|
Age (years), mean ± SD | 61 ± 11 | 60 ± 10 | 59 ± 11 | 58 ± 13 | 0.2908 |
Gender Male n (%) | 256 (53) | 24 (47) | 28 (62) | 14 (78) | 0.0866 |
BMI (kg/m2) n (%) | |||||
≥ 30 | 74 (15) | 10 (20) | 7 (16) | 2 (11) | 0.9531 |
< 18.5 | 12 (2) | 2 (4) | 0 (0) | 0 (0) | |
[25–30[ | 163 (34) | 14 (27) | 17 (38) | 7 (39) | |
[18.5–25[ | 233 (48) | 25 (49) | 21 (47) | 9 (50) | |
Chronic hepatitis duration (years), mean ± SD | 16 ± 8 | 15 ± 7 | 16 ± 9 | 11 ± 8 | 0.0814 |
HCV genotype n (%) | |||||
1a | 110 (23) | 11 (22) | 14 (31) | 6 (33) | 0.2543 |
4 | 99 (20) | 17 (33) | 10 (22) | 6 (33) | |
1 not subtyped | 25 (5) | 1 (2) | 3 (7) | 0 (0) | |
1b | 251 (52) | 22 (43) | 18 (40) | 6 (33) | |
Diabetes n (%) | 104 (21) | 7 (14) | 9 (20) | 1 (6) | 0.2710 |
Hypertension n (%) | 194 (40) | 25 (49) | 18 (40) | 4 (22) | 0.2571 |
Cirrhosis n (%) | 259 (54) | 33 (65) | 27 (60) | 16 (89) |
0.0117
|
•Child-Pugh score B or C | 17 (7) | 8 (24) | 1 (4) | 2 (13) |
0.0083
|
•MELD ≥15 | 19 (8) | 4 (13) | 1 (4) | 3 (19) | 0.2444 |
•Elastography ≥14.5 kPa | 131 (51) | 15 (45) | 14 (52) | 10 (63) | 0.7540 |
•Fibrotest ≥0.73 | 70 (27) | 10 (30) | 11 (41) | 10 (63) |
0.0175
|
•Liver biopsy > 2 years | 148 (57) | 20 (61) | 14 (52) | 7 (44) | 0.6618 |
•Liver biopsy < 2 years | 18 (7) | 2 (6) | 1 (4) | 0 (0) | 0.9306 |
Decompensated cirrhosis n (%) | 16 (3) | 6 (12) | 2 (4) | 0 (0) |
0.0483
|
•Child-Pugh score B or C | 6 (38) | 4 (67) | 1 (50) | 0.5589 | |
•MELD score, mean ± SD | 9.7 ± 2.9 | 12.3 ± 3.9 | 12.5 ± 0.7 | 0.1793 | |
Albumin (< 30 g/L) n (%) | 12 (3) | 5 (11) | 1 (3) | 1 (6) |
0.0415
|
Prothrombin time (≤70%) n (%) | 45 (10) | 11 (22) | 6 (14) | 6 (33) |
0.0037
|
AST (> 5 x ULN) n (%) | 28 (6) | 4 (8) | 3 (7) | 2 (12) | 0.4951 |
ALT (> 5 x ULN) n (%) | 31 (6) | 2 (4) | 1 (2) | 1 (6) | 0.7735 |
Haemoglobin (≤12 g/dL in women or ≤ 13 g/dL in men) n (%) | 58 (12) | 8 (16) | 5 (11) | 1 (6) | 0.7365 |
Platelets < 100,000/mm3 | 87 (19) | 15 (30) | 11 (25) | 8 (47) |
0.0109
|
Bilirubin conj ≥5 μmol/L | 133 (52) | 20 (63) | 16 (57) | 13 (100) |
0.0021
|
Treatment history n (%) | |||||
•Naïve patients | 141 (29) | 13 (25) | 14 (31) | 5 (28) | 0.0618 |
•Experienced patients, last treatment PEG/RBV | 324 (67) | 35 (69) | 25 (56) | 10 (56) | |
•Experienced patients, last treatment 1rst generation PI/PEG/RBV | 20 (4) | 3 (6) | 6 (13) | 3 (17) | |
Response profile in treatment experienced patients | |||||
•Unknown | 164 (48) | 20 (53) | 17 (55) | 6 (46) | 0.8370 |
•Responders | 86 (25) | 9 (24) | 4 (13) | 3 (23) | |
•Not responders | 94 (27) | 9 (24) | 10 (32) | 4 (31) |
Efficacy
TOTAL N = 599 | Sofosbuvir + simeprevir | Sofosbuvir + simeprevir + ribavirin | Fisher p value | CMH p value (strati-fication: 12 weeks vs 24 weeks) | CMH p value (strati-fication: RBV vs no RBV) | |||
---|---|---|---|---|---|---|---|---|
12 weeks n = 485 | 24 weeks n = 51 | 12 weeks n = 45 | 24 weeks n = 18 | |||||
Negative HCV RNA | ||||||||
Week 12 n/N (%) | 519/576 (90) | 422/469 (90) | 41/47 (87) | 43/44 (98) | 13/16 (81) | 0.1312 | 0.2779 | 0.1514 |
Week 24n/N (%) | 60/65 (92) | 44/49 (90) | 16/16 (100) | 0.3219 | 0.1869 | |||
Follow up week 4n/N (%) | 277/570 (49) | 318/341 (93) | 30/31 (97) | 39/40 (98) | 13/13 (100) | 0.7525 | 0.2341 | 0.3669 |
SVR 12 (imputeda) n/N (%) | 555/599 (93) | 449/485 (93) | 46/51 (90) | 44/45 (98) | 16/18 (89) | 0.3742 | 0.3197 | 0.2538 |
SVR 24 n/N (%) | 459/473 (97) | 374/385 (97) | 38/40 (95) | 37/38 (97) | 10/10 (100) | 0.7360 | 0.6713 | 0.6102 |
SVR 12 in non cirrhotic patients n/N (%) | 244/257 (95) | 206/219 (94) | 18/18 (100) | 18/18 (100) | 2/2 (100) | 0.5937 | 0.2887 | 0.2887 |
SVR 12 in cirrhotic patients n/N (%) | 304/335 (91) | 236/259 (91) | 28/33 (85) | 26/27 (96) | 14/16 (88) | 0.4043 | 0.3882 | 0.1293 |
SVR 12 in treatment naïve patientsn/N (%) | 160/173 (92) | 130/141 (92) | 12/13 (92) | 14/14 (100) | 4/5 (80) | 0.3637 | 0.6195 | 0.4809 |
SVR 12 in treatment experienced patients n/N (%) | 395/426 (93) | 319/344 (93) | 34/38 (89) | 30/31 (97) | 12/13 (92) | 0.6749 | 0.3874 | 0.3635 |
Last treatment | ||||||||
PEG/RBV n/N (%) | 365/394 (93) | 300/324 (93) | 32/35 (91) | 24/25 (96) | 9/10 (90) | 0.8073 | 0.6462 | 0.6214 |
First generation PI/PEG/RBV n/N (%) | 30/32 (94) | 19/20 (95) | 2/3 (67) | 6/6 (100) | 3/3 (100) | 0.3750 | 0.2637 | 0.1122 |
Response profile | ||||||||
Not respondersn/N (%) | 108/117 (92) | 87/94 (93) | 8/9 (89) | 9/10 (90) | 4/4 (100) | 0.6151 | 0.9339 | 0.9864 |
Respondersb n/N (%) | 99/102 (97) | 84/86 (98) | 8/9 (89) | 4/4 (100) | 3/3 (100) | 0.4040 | 0.5154 | 0.1537 |
Unknown n/N (%) | 188/207 (91) | 148/164 (90) | 18/20 (90) | 17/17 (100) | 5/6 (83) | 0.4343 | 0.3647 | 0.5569 |
SVR 12 in Cirrhotic Treatment experienced patients n/N(%) | 230/258 (89) | 178/200 (89) | 23/27 (85) | 18/19 (95) | 11/12 (92) | 0.8219 | 0.3407 | 0.5044 |
SVR 12 in patients with genotype 1a n/N (%) | 127/141 (90) | 99/110 (90) | 10/11 (91) | 13/14 (93) | 5/6 (83) | 0.8660 | 0.9608 | 0.7862 |
SVR 12 in patients with genotype 1b infection n/N (%) | 280/297 (94) | 237/251 (94) | 20/22 (91) | 18/18 (100) | 5/6 (83) | 0.2403 | 0.6111 | 0.2015 |
SVR 12 in patients with genotype 4 infection n/N (%) | 121/132 (92) | 89/99 (90) | 16/17 (94) | 10/10 (100) | 6/6 (100) | 0.9150 | 0.2283 | 0.5850 |
SVR 12 in patients with genotype 1 not subtyped n/N (%) | 27/29 (93) | 24/25 (96) | 0/1 (0) | 3/3 (100) | 0.0764 | 0.7290 | 0.0005 |
n with SVR 12 / Total (%): Yes VS Reference | Univariate | Multivariate | |||
---|---|---|---|---|---|
OR (95% CI) | p-Value | OR (95% CI) | p-Value | ||
Ribavirin containing regimen (reference: no RBV) | 60/63 (95) VS 495/536 (92) | 1.66 (0.5–8.61) | 0.5936 | ||
Treatment duration 24 weeks (reference: 12 weeks) | 62/69 (90) VS 493/530 (93) | 0.67 (0.28–1.85) | 0.4654 | ||
Cirrhosis (reference: no cirrhosis) | 304/335 (91) VS 244/257 (95) | 0.52 (0.25–1.06) | 0.0734 | 1.07 (0.36–3.20) | 1.0000 |
Conjugated bilirubin ≥5 μmol/L (reference: < 5 μmol/L) | 163/182 (90) VS 141/148 (95) | 0.43 (0.15–1.1) | 0,0835 | 0.58 (0.19–1.67) | 0.3701 |
TP ≤ 70% (reference: > 70%) | 59/68 (87) VS 458/491 (93) | 0.47 (0.21–1.18) | 0.1103 | 0.41 (0.14–1.22) | 0.1148 |
Hemoglobin ≤12 g/dL for women or ≤ 13 g/dL for men(reference: > 12 g/dL or > 13 g/dL) | 63/72 (88) VS 480/514 (93) | 0.5 (0.22–1.23) | 0.1338 | 0.59 (0.22–1.71) | 0.3620 |
Platelets < 100,000/mm3 (reference: ≥ 100,000/mm3) | 108/121 (89) VS 429/458 (94) | 0.56 (0.27–1.22) | 0.1505 | 1.12 (0.39–3.38) | 1.0000 |
Genotype 1b (reference: 1 not subtyped or 1a or 4) | 280/297 (94) VS 275/302 (91) | 1.62 (0.83–3.24) | 0.1757 | 0.94 (0.39–2.26) | 1.0000 |
Male (reference: Female) | 303/322 (94) VS 252/277 (91) | 1.18 (0.65–2.13) | 0.6504 | 1.62 (0.68–3.94) | 0.3192 |
Genotype 1a (reference: 1 not subtyped or 1b or 4) | 127/141 (90) VS 428/458 (93) | 0.64 (0.32–1.34) | 0.2489 | ||
Neutrophil < 1500/mm3 (reference: ≥ 1500/mm3) | 33/38 (87) VS 503/540 (93) | 0.49 (0.17–1.69) | 0.2641 | ||
Chronic hepatitis duration ≥15 years (reference: < 15 years) | 308/337 (91) VS 236/251 (94) | 0.68 (0.33–1.34) | 0.2980 | ||
Albumin < 30 g/L (reference: ≥ 30 g/L) | 16/19 (84) VS 479/519 (92) | 0.45 (0.12–2.49) | 0.3756 | ||
Age > 65 years (reference: ≤ 65 years) | 209/223 (94) VS 346/376 (92) | 1.29 (0.65–2.7) | 0.5478 | ||
MELD ≥15 (reference: < 15) | 31/35 (89) VS 454/491 (92) | 0.63 (0.21–2.6) | 0.5732 | ||
Genotype 4 (reference: 1a or 1b or 1 not subtyped) | 121/132 (92) VS 434/467 (93) | 0.84 (0.4–1.89) | 0.7409 | ||
Viral load < 6 M at beginning of treatment (reference: ≥ 6 M) | 502/542 (93) VS 42/44 (95) | 0.6 (0.07–2.45) | 0.7425 | ||
ALAT > 5 ULN (reference: ≤ 5ULN) | 33/35 (94) VS 511/551 (93) | 1.29 (0.31–11.5) | 0.9999 | ||
ASAT > 5 ULN (reference: ≤ 5ULN) | 34/37 (92) VS 508/547 (93) | 0.87 (0.26–4.63) | 0.9999 | ||
Decompensated cirrhosis (reference: no decompensated cirrhosis) | 22/24 (92) VS 533/575 (93) | 0.87 (0.2–7.86) | 0.9999 | ||
Treatment experienced (reference: treatment naïve) | 160/173 (92) VS 395/426 (93) | 0.97 (0.48–2.07) | 0.9999 | ||
Genotype 1 not subtyped (reference: 1a or 1b or 4) | 27/29 (93) VS 528/570 (93) | 1.07 (0.25–9.63) | 0.9999 | ||
Previous treatment: PEG/RBV (reference: 1st generation PI/PEG/RBV or none) | 365/394 (93) VS 190/205 (93) | 0.99 (0.48–1.97) | 0.9999 |
Safety and tolerability
Sofosbuvir + simeprevir | Sofosbuvir + simeprevir+ ribavirin | Fisher P-value | CMH P value (stratification: 12 weeks vs 24 weeks) | CMH P value (stratification: RBV vs no RBV) | |||
---|---|---|---|---|---|---|---|
12 weeks | 24 weeks | 12 weeks | 24 weeks | ||||
Number of patients | 485 | 51 | 45 | 18 | |||
Treatment interruptions n (%) | 6 (1) | 4 (8) | 5 (11) | 3 (17) | 0.0000 | 0.0003 | 0.0130 |
‐ Adverse event | 3 (1) | 2 (4) | 3 (7) | 1 (6) | 0.0030 | 0.0074 | 0.2081 |
‐ Other reasons | 3 (1) | 2 (4) | 2 (4) | 2 (11) | 0.0014 | 0.0169 | 0.0300 |
All adverse events - any n (%) | 312 (64) | 35 (69) | 32 (71) | 15 (83) | 0.3185 | 0.1720 | 0.3247 |
(Maximum grade) | |||||||
‐ Grade 1 | 156 (32) | 15 (29) | 9 (20) | 3 (17) | < 0.0001 | 0.0043 | < 0.0001 |
‐ Grade 2 | 116 (24) | 7 (14) | 19 (42) | 10 (56) | |||
‐ Grade 3 | 28 (6) | 3 (6) | 2 (4) | 0 (0) | |||
‐ Grade 4 | 11 (2) | 8 (16) | 2 (4) | 1 (6) | |||
‐ Grade 5 | 1 (0) | 2 (4) | 0 (0) | 1 (6) | |||
Deaths | 1 (0) | 2 (4) | 0 (0) | 1 (6) | 0.0096 | 0.8684 | 0.0003 |
Other serious adverse events | 26 (5) | 7 (14) | 3 (7) | 1 (6) | 0.1241 | 0.7697 | 0.0453 |
Adverse Events (≥10% in any subgroup) | |||||||
‐ Asthenia | 80 (16) | 11 (22) | 17 (38) | 4 (22) | 0.0074 | 0.0023 | 0.9114 |
‐ Headache | 69 (14) | 2 (4) | 3 (7) | 4 (22) | 0.0457 | 0.7803 | 0.2836 |
‐ Pruritus | 42 (9) | 1 (2) | 3 (7) | 3 (17) | 0.1653 | 0.5673 | 0.3966 |
‐ Hyperbilirubinaemia | 28 (6) | 5 (10) | 7 (16) | 5 (28) | 0.0015 | 0.0018 | 0.1129 |
‐ Fatigue | 33 (7) | 2 (4) | 0 (0) | 2 (11) | 0.1531 | 0.2982 | 0.9563 |
‐ Thrombocytopenia | 20 (4) | 7 (14) | 2 (4) | 3 (17) | 0.0059 | 0.7737 | 0.0007 |
‐ Insomnia | 24 (5) | 2 (4) | 3 (7) | 2 (11) | 0.4667 | 0.3140 | 0.9557 |
‐ Sleep disorder | 21 (4) | 2 (4) | 1 (2) | 3 (17) | 0.1160 | 0.6041 | 0.3077 |
‐ Dry skin | 7 (1) | 0 (0) | 1 (2) | 2 (11) | 0.0526 | 0.0711 | 0.6618 |
‐ Oedema peripheral | 4 (1) | 2 (4) | 0 (0) | 2 (11) | 0.0117 | 0.5464 | 0.0028 |
‐ Eczema | 3 (1) | 2 (4) | 0 (0) | 2 (11) | 0.0059 | 0.4760 | 0.0012 |
‐ Dyspnoea | 1 (0) | 2 (4) | 1 (2) | 2 (11) | 0.0004 | 0.0586 | 0.0019 |
‐ Gastrointestinal disorder | 4 (1) | 0 (0) | 0 (0) | 2 (11) | 0.0336 | 0.1701 | 0.2244 |
‐ Jaundice | 0 (0) | 1 (2) | 2 (4) | 2 (11) | 0.0001 | 0.0003 | 0.0579 |