Abstract
INTRODUCTION
Clinical trials and real-world experiences evaluating ombitasvir/paritaprevir/ritonavir (OMV/PTV/r) ± dasabuvir (DSV) ± ribavirin (RBV) combination therapy have shown excellent rates of sustained virological response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 or 4 infections. We aimed to investigate the effectiveness and safety of OMV/PTV/r ± DSV ± RBV combination regimen in a real-world clinical practice.
METHODS
Data from HCV genotype 1 and 4 patients treated with OMV/PTV/r ± DSV ± RBV (n=862) in 34 centers across Turkey between April 1, 2017 and August 31, 2018 were recorded in a large national database. Study patients were treatment-naïve or interferon plus RBV-experienced with or without compensated cirrhosis. Follow-up (FU) ranged from 24 to 36 weeks depending on-treatment duration. Demographic, clinical and virological data were analyzed. Details of clinical and laboratory adverse events (AEs) were recorded.
RESULTS
The mean age of the patients was 55.63 and 430 (49.9%) were male. The majority had HCV genotype 1b infection (77.3%), and 66.2% were treatment-naïve. Non-cirrhosis was present at baseline in 789 patients (91.5%). The HCV RNA level was below 800.000 IU/mL in 442 of the cases. Of all patients, 18 had hepatitis B virus (HBV) co-infection. Sixty-five percent of the patients had an underlying disease. Out of the 862 analysed patients, 57 patients did not return for viral load FU at 12 weeks, 6 patients stopped antiviral therapy because of AEs, 7 patients had virological failure and 1 patient died. Virological rates by per protocol analysis was calculated in the patients. SVR12 rate was 99.1% in all patients. No significant differences were observed in SVR12 according to HCV genotypes (p= 0.410). HCV RNA was undectable at treatment week 4 in 90.9%, at treatment week 8 in 98.5%, and at end of treatment (EOT) in 98.9%. No significant differences were observed in at treatment week 8 and EOT virological response according to HCV genotypes (p= 0.630, p= 0.785, respectively). Rates of rapid virological response (RVR) were significantly higher in the patients infected with HCV genotype 1a or 1b than in the patients infected with genotype 4 (p< 0.001). RVR and SVR12 ratios were significantly higher in non-cirrhotic patients compared to compensated cirrhotic patients (p= 0.004, p=0.016). There was not significant difference in on-treatment or EOT or FU12 weeks responses between treatment-naïve and treatment-experienced patients (p= 0.599, p= 0.166, p= 1000, p=0.431). Rates of AEs and AEs-associated treatment discontinuation were 59.7% and 0.7% in the patients, respectively. HBV reactivation occurred in 13.3% of the patients.
CONCLUSION
The present real-life data of Turkey for OBV/PTV/r ± DSV ± RBV treatment of patients with HCV genotype 1b, 1a or 4 infection from 862 patients demonstrated high efficacy and a safety profile.
Keywords: Chronic hepatitis C, HCV genotypes 1 and 4, ombitasvir, paritaprevir, dasabuvir, real-world effectiveness
Figure 1.
Study Flowchart
Figure 2.
Rates of virological response to ombitasvir paritaprevir ritonavir dasabuvir ribavirin
Table 1.
Baseline demographical and clinical characteristics
| Patient characteristics | Genotype 1a (n= 141) | Genotype 1b (n= 666) | Genotype 4 (n= 55) | Total (n= 862) |
|---|---|---|---|---|
| Gender (male), n (%) | 94 (66.7) | 307 (46.1) | 29 (52.7) | 430 (49.9) |
| Age (years) | 49.60 ± 15.61 | 56.94 ± 14.15 | 55.22 ± 14.93 | 55.63 ± 14.68 |
| (19.00–85.00) | (18.00–87.00) | (23.00–85.00) | (18.00–87.00) | |
| Treatment-naïve, n (%) | 94 (66.7) | 439 (65.9) | 38 (69.1) | 571 (66.2) |
| Non-cirrhotic | 88 (93.6 | 406 (92.5) | 29 (76.3) | 523 (91.6) |
| Compensated cirrhotic | 6 (6.4) | 33 (7.5) | 9 (23.7) | 48 (8.4) |
| Treatment-experienced, n (%) | 47 (33.3) | 227 (34.1) | 17 (30.9) | 291 (33.8) |
| Non-cirrhotic | 45 (95.7) | 205 (90.3) | 16 (94.1) | 266 (91.4) |
| Compensated cirrhotic | 2 (4.3) | 22 (9.7) | 1 (5.9) | 25 (8.6) |
| HCV RNA, log10 IU/mL | 5.88 ± 0.81 | 5.81 ± 0.86 | 6.09 ± 0.66 | 5.84 ± 0.84 |
| (3.53–7.61) | (3.11–7.69) | (4.46–7.22) | (3.11–7.69) | |
| ≥ 800.000, IU/L, n (%) | 71 (50.4) | 310 (46.5) | 39 (70.9) | 420 (48.7) |
| ALT, IU/L | 44.00 (30.00–68.00) | 41.00 (27.00–63.00) (nmd=3) | 32.00 (22.00–56.00) | 41.00 (27.00–63.00) |
| AST, IU/L | 36.00 (27.00–53.00) | 37.00 (26.00–54.00) (nmd=3) | 31.00 (21.00–53.00) | 36.00 (26.00–54.00) |
| Total bilirubin, mg/dL | 0.69 (0.51–0.97) (nmd=12) | 0.65 (0.49–0.83) (nmd=93) | 0.73 (0.55–0.98) (nmd=3) | 0.66 (0.49–0.87) |
| Albumin, g/dL | 4.28 ± 0.4 (3.00–5.60) (nmd=13) | 4.23 ± 0.44 (2.60–5.70) (nmd=86) | 4.14 ± 0.56 (3.00–5.60 (nmd=4)) | 4.23 ± 0.45 (2.90–5.70) |
| Haemoglobin, g/dL | 13.95 ± 1.76 (10.00–17.80) (nmd=11) | 13.84 ± 1.63 (8.20–18.80) (nmd=44) | 13.91 ± 1.97 (10.40–17.90) | 13.86 ± 1.68 (8.20–18.80) |
| Platelets count, /1000 mm3 | 209.50 (170.00–265.25) (nmd=7) | 216.00 (168.00–264.00) (nmd=27) | 216.00 (165.00–262.00) | 215.00 (168.00–264.00) |
| INR | 1.10 (1.00–1.22) (nmd=5) | 1.01 (0.95–1.10) (nmd=42) | 1.00 (0.94–1.16) (nmd=2) | 1.02 (0.96–1.10) |
| Fibrosis stage*, n (%) | ||||
| F0 | - | 5 (0.8) | - | 5 (0.6) |
| F1 | 12 (8.5) | 82 (12.3) | 7 (12.7) | 101 (11.7) |
| F2 | 29 (20.6) | 134 (20.1) | 5 (9.1) | 168 (19.5) |
| F3 | 35 (24.8) | 179 (26.9) | 14 (25.5) | 228 (26.5) |
| F4 | 3 (2.1) | 19 (2.9) | 1 (1.8) | 23 (2.7) |
| F5 | 3 (2.1) | 28 (4.2) | 6 (10.9) | 34 (3.9) |
| F6 | 3 (2.1) | 11 (1.7) | 3 (5.5) | 20 (2.3) |
| Unknown | 56 (39.7) | 208 (31.2) | 19 (34.5) | 283 (32.8) |
| Antiviral treatment history n (%) | ||||
| Number of experience | ||||
| 1 | 40 (85.1) | 157 (69.2) | 16 (94.1) | 213 (73.2) |
| >1 | 7 (14.9) | 70 (30.8) | 1 (5.9) | 78 (26.8) |
| Treatment regimens | ||||
| PegINF+RBV | 35 (74.5) | 145 (63.9) | 16 (94.1) | 196 (67.4) |
| PegINF+RBV/Peg INF+RBV | 6 (12.8) | 66 (9.9) | 1 (5.9) | 73 (25.1) |
| INF + RBV | 5 (10.6) | 12 (5.3) | - | 17 (5.8) |
| INF+RBV/PegINF+RBV | 1 (2.1) | 4 (1.8) | - | 5 (1.7) |
| Treatment responses | ||||
| Relapsers | 11 (23.4) | 84 (37.0) | 6 (35.3) | 101 (34.7) |
| Non-responders | 6 (12.8) | 65 (28.6) | 8 (47.1) | 79 (27.1) |
| Discontinued due to AEs | 2 (4.3) | 18 (7.9) | 1 (5.9) | 21 (7.2) |
| Parsiel responders | 3 (6.4) | 4 (1.8) | - | 7 (2.4) |
| Breaktrough | - | 2 (0.9) | 1 (5.9) | 3 (1.0) |
| Unknown | 25 (53.2) | 54 (23.8) | 1 (5.9) | 80 (27.5) |
| HBV co-infection, n (%) | 2 (1.4) | 15 (2.3) | 1 (1.8) | 18 (2.1) |
| HIV co- infection, n (%) | 1 (0.7) | 1 (0.2) | 2 (3.6) | 4 (0.5) |
| HBV-HDV co-infection, n (%) | - | 1 (0.2) | - | 1 (0.1) |
| Associated diseases n (%) | 62 (44.0) | 452 (67.9) | 43 (78.2) | 557 (64.6) |
| Number of diseases | ||||
| 1 | 46 (74.2) | 310 (68.6) | 28 (65.1) | 384 (68.9) |
| >1 | 16 (25.8) | 142 (31.4) | 15 (34.9) | 173 (31.1) |
| Definition of disease | ||||
| Cardiovascularπ | 28 (19.9) | 164 (24.6) | 11 (20.0) | 203 (23.5) |
| Diabetes mellitus | 16 (11.3) | 76 (11.4) | 12( 21.8) | 104 (12.1) |
| Chronic renal failure | 15 (10.6) | 51 (7.7) | 11 (20.0) | 77 (8.9) |
| Lung diseasesΦ | 7 (5.0) | 39 (5.9) | 1 (1.8) | 47 (5.5) |
| Hematologic diseases# | - | 17 (2.6) | 4 (7.3) | 21 (2.4) |
| Neurological diseasesη | 4 (2.8) | 16 (2.4) | 1 (1.8) | 21 (2.4) |
| Psychiatric diseasesϕ | 3 (2.1) | 16 (2.4) | 1 (1.8) | 20 (2.3) |
| Thyroid diseasesω | 3 (2.1) | 16 (2.4) | 1 (1.8) | 20 (2.3) |
| Oncologic diseasesμ | 2 (1.4) | 14 (2.1) | - | 16 (1.9) |
| Bone-joint diseasesα | - | 10 (1.5) | - | 10 (1.2) |
| Dermatological diseasesγ | - | 7 (1.1) | 1 (1.8) | 8 (0.9) |
| Substance use | 1 (0.7) | 6 (0.9) | - | 7 (0.8) |
| Kidney transplantations | 1 (0.7) | 3 (0.5) | 2 (3.6) | 6 (0.7) |
| Rheumatologic diseasesβ | 1 (0.7) | 3 (0.5) | - | 4 (0.5) |
| Otherυ | 2 (1.4) | 49 (7.4) | 3 (5.5) | 54 (6.3) |
| Modification of concomitant medications, n (%) | 35 (24.8) | 62 (9.3) | 16 (29.1) | 113 (13.1) |
Table 2.
Virological responses according to patients characteristics
| Virological responses [negative/tested (%)] | ||||
|---|---|---|---|---|
| Variable | Week 4 (RVR) | Week 8 | EOT | Week 12 (SVR12) |
| All patients | 690/759 (90.9) | 596/605 (98.5) | 779/788 (98.9) | 791/798 (99.1) |
| Genotypes | ||||
| Genotype 1a (n=141) | 119/123 (96.7%)a | 108/109 (99.1) | 132/133 (99.2) | 125/127 (98.4) |
| Genotype 1b (n=666) | 533/587 (90.8%)a | 455/463 (98.3) | 597/604 (98.8) | 616/620 (99.4) |
| Genotype 4 (n:55) | 38/49 (77.6%)b | 33/33 (100) | 50/51 (98.0) | 50/51 (98.0) |
| p value | < 0.001 | 0.630 | 0.785 | 0.410 |
| Non-cirrhotic/compensated cirrhotic | ||||
| Non-cirrhotic (n=789) | 633/689 (91.9) a | 543/551 (98.5) | 713/720 (99.0) | 727/731 (99.5) |
| Compensated cirrhotic (n=73) | 57/70 (81.4) b | 53/54 (98.1) | 66/68 (97.1) | 64/67 (95.5) |
| p value | 0.004 | 0.571 | 0.178 | 0.016 |
| Response of previous therapy | ||||
| Treatment-naïve (n=571) | 438/484 (90.5) | 376/384 (97.9) | 506/512 (98.8) | 510/516 (98.8) |
| Treatment-experienced (n=291) | 252/275 (91.6) | 220/221 (99.5) | 273/276 (98.9) | 281/282 (99.6) |
| p value | 0.599 | 0.166 | 1.000 | 0.431 |
Table 3.
Median laboratory parameters changes between baseline and 12 weeks post-treatment
| Variables | Follow-up time points | |||||
|---|---|---|---|---|---|---|
| Baseline | Week 4 | Week 8 | Week 12 | FU12 | p value | |
| Genotype 1a (n= 127) | ||||||
| ALT, IU/L (number of complete cases= 94) | 44.50 (30.75–67.50)a | 25.50 (15.75–43.00)b | 22.00 (12.68–34.50)b | 20.00 (14.00–33.00)b | 25.00 (16.00–33.00)b | <.001 |
| AST, IU/L ( number of complete cases= 91) | 39.00 (29.00–54.00)a | 25.00 (17.00–38.00)b | 22.00 (15.00–33.00)cd | 18.00 (13.00–29.00)c | 25.00 (17.00–33.00)bd | <.001 |
| Haemoglobin, g/dL (number of complete cases= 63) | 13.88 ± 1.90a | 12.91 ± 1.99bc | 12.71 ± 2.35bc | 12.58 ± 1.92b | 13.14 ± 1.98c | <.001 |
| Platelets count, /1000 mm3 (number of complete cases= 78) | 209.5 (166.8–272.0) | 219.0 (175.5–278.0) | 217.0 (174.8–267.3) | 221.5 (177.5–272.0) | 222.5 (197.0–288.3) | .088 |
| Genotype 1b (n= 620) | ||||||
| ALT, IU/L (number of complete cases= 485) | 41.00 (28.00–62.50)a | 19.00 (13.00–34.00)b | 17.00 (12.00–30.00)c | 16.00 (12.00–24.00)d | 18.00 (13.00–27.00)c | <.001 |
| AST, IU/L (number of complete cases= 482) | 37.00 (25.75–54.00)a | 21.00 (16.58–32.00)b | 19.0 0 (16.00–27.00)c | 18.00 (15.00–25.00)d | 20.00 (16.00–25.00)c | <.001 |
| Haemoglobin, g/dL (number of complete cases = 401) | 13.81 ± 1.64ab | 13.83 ± 1.67a | 13.71 ± 1.71b | 13.66 ± 1.71b | 13.79 ± 1.68b | .002 |
| Platelets count, /1000 mm3 (number of complete cases= 422) | 215.0 (164.8–260.0)a | 217.0 (178.0–262.5)b | 214.0 (171.0–257.0)a | 219.5 (176.8–264.0)b | 216.0 (178.0–266.0)b | .001 |
| Genotype 4 (n= 51) | ||||||
| ALT, IU/L (number of complete cases= 48) | 32.00 (22.25–55.50)a | 16.00 (12.00–27.50)b | 14.50 (11.25–19.75)b | 15.00 (12.00–19.75)b | 17.00 (12.00–23.00)b | <.001 |
| AST, IU/L (number of complete cases= 48) | 31.00 (21.25–53.00)a | 18.00 (14.00–22.00)b | 16.00 (12.00–21.75)b | 16.00 (12.00–19.00)b | 18.50 (14.00–22.75)b | <.001 |
| Haemoglobin, g/dL (number of complete cases= 48) | 14.07 ± 2.04a | 13.19 ± 2.33b | 13.00 ± 2.13b | 12.85 ± 2.08b | 13.28 ± 2.20b | <.001 |
| Platelets count, /1000 mm3 (number of complete cases= 48) | 217.0 (167.5–269.5) | 242.0 (192.3–295.8) | 220.5 (187.0–282.5) | 231.5 (186.3–284.5) | 237.0 (186.0–278.0) | .081 |
| Total (n= 798) | ||||||
| ALT, IU/L (number of complete cases= 627) | 41.00 (28.00–64.00)a | 20.00 (13.00–34.00)b | 17.00 (12.00–31.00)c | 17.00 (12.00–25.00)d | 19.00 (13.00–27.00)c | <.001 |
| AST, IU/L (number of complete cases= 621) | 37.00 (26.00–54.00)a | 21.00 (16.00–32.00)b | 19.00 (15.00–27.00)c | 18.00 (14.00–24.00)d | 20.00 (16.00–26.00)c | <.001 |
| Haemoglobin, g/dL (number of complete cases= 512) | 13.84 ± 1.71a | 13.65 ± 1.81b | 13.52 ± 1.88b | 13.45 ± 1.81b | 13.67 ± 1.79b | <.001 |
| Platelets count, /1000 mm3 (number of complete cases= 548) | 214.0 (166.0–261.0)a | 217.5 (178.0–267.0)b | 214.0 (175.0–259.5)b | 220.0 (177.3–267.0)b | 218.5 (181.3–269.8)b | <.001 |
Table 4.
Demographic and clinical characteristics of patients with virolojik failure
| Patient No. 1 | Patient No. 2 | Patient No. 3 | Patient No. 4 | Patient No. 5 | Patient No. 6 | Patient No. 7 | |
|---|---|---|---|---|---|---|---|
| Gender | Male | Female | Male | Female | Male | Female | Male |
| Age, years | 42 | 66 | 52 | 65 | 65 | 66 | 58 |
| Genotype | 1a | 1a | 1b | 1b | 1b | 1b | 4 |
| Response of current therapy | Relapser | Relapser | Relapser | Non-responder | Non-responder | Non-responder | Non-responder |
| Previous antiviral treatment | Treatment-naïve, non-cirrhotic | Treatment-naïve, compensated cirrhotic | Treatment-naïve, non-cirrhotic | Treatment-naïve, non-cirrhotic | Treatment-naïve, non-cirrhotic | Treatment-experienced, compensated cirrhotic | Treatment-naïve, compensated cirrhotic |
| HCV RNA, IU/mL | |||||||
| Day 0 | 1.314.359 | 1.142.000 | 6.318.000 | 428.400 | 2.560.000 | 3.800.000 | 540.000 |
| Week 4 | - | Undetected | 118000 | - | 511 | 2.700.000 | 5.139.000 |
| Week 8 | Undetected | Undetected | Undetected | 127.000 | Undetected | 4.200.000 | Undetected |
| Week 12 | Undetected | Undetected | Undetected | 298.000 | 6.390 | 5.870.000 | 3156000 |
| FU 12 | 857.845 | 2.680.000 | 4.567.000 | 527.000 | 487.000 | 3.990.000 | 6.177.000 |
| ALT | 27 | 89 | 22 | 123 | 36 | 99 | 59 |
| AST | 19 | 103 | 22 | 100 | 30 | 157 | 67 |
| Hemoglobin | 14 | 12.10 | 16.20 | 13.10 | 14.30 | 12 | 13.10 |
| Platelet count | 161.000 | 90.000 | 219.000 | 176.000 | 255.555 | 64.000 | 100.000 |
Table 5.
Adverse events and laboratory abnormalities
| Patients, n (% patients with at least one event or one laboratory abnormalities)/Total patients | Genotype 1a (n= 141) | Genotype 1b (n= 666) | Genotype 4 (n= 55) | Total (n= 862) |
|---|---|---|---|---|
| Any AEs | 93 (66.0) | 384 (57.7) | 38 (69.1) | 515 (59.7) |
| AEs or laboratory abnormalities leading to treatment discontinuation | - | 4 (0.60) | 2 (3.6) | 6 (0.7) |
| Adverse events | ||||
| Asthenia | 17 (12.1) | 68 (10.2) | 5 (9.1) | 90 (10.4) |
| Pruritus | 9 (6.4) | 38 (5.7) | 2 (3.6) | 49 (5.7) |
| Headache | 7 (5.0) | 38 (5.7) | 1 (1.8) | 46 (5.3) |
| Fatigue | 7 (5.0) | 34 (5.1) | 3 (5.5) | 44 (5.1) |
| Nausea | 4 (2.8) | 34 (5.1) | 1 (1.8) | 39 (4.5) |
| Insomnia | 5 (3.5) | 18 (2.7) | - | 23 (2.7) |
| Anorexia | 2 (1.4) | 18 (2.7) | 2 (3.6) | 22 (2.6) |
| Diarrhea | 4 (2.8) | 10 (1.5) | 2 (3.6) | 16 (1.9) |
| Dizziness | 3 (2.1) | 11 (1.7) | - | 14 (1.6) |
| Mild rash | 3 (2.1) | 4 (0.6) | 3 (5.5) | 10 (1.2) |
| Abdominal pain | - | 8 (1.2) | - | 8 (0.9) |
| Cough | - | 6 (0.9) | 1 (1.8) | 7 (0.8) |
| Feverα | - | 6 (0.9) | - | 6 (0.7) |
| Arthralgia | 1 (0.7) | 4 (0.6) | - | 5 (0.6) |
| Dry skin | 4 (2.8) | - | 1 (1.8) | 5 (0.6) |
| Palpitation | 2 (1.4) | 1 (0.2) | - | 3 (0.3) |
| Vomiting | - | 1 (0.2) | 1 (1.8) | 2 (0.2) |
| Chest pain | 2 (0.3) | 2 (0.2) | ||
| Otherαα | 1 (0.7) | 37 (5.6) | - | 38 (4.4) |
| Haemoglobin | ||||
| <10 – 8 g/dL | 14 (9.9) | - | 7 (12.7) | 21 (2.4) |
| <8 – 6.5 g/dL | 2 (1.4) | - | 1 (1.8) | 3 (0.3) |
| Total bilirubin | ||||
| >1.5 – 3 × ULN | 6 (4.3) | 28 (4.2) | 4 (7.3) | 38 (4.40) |
| >3 – 10 × ULN | - | 2 (0.3)βμ | 2 (3.6)βμ | 4 (0.5) |
| ALT | ||||
| >3 – 5 × ULN | 1 (0.7) | 7 (1.1) | - | 8 (0.9) |
| >5 – 20 × ULN | - | 1 (0.2)β | 1 (1.8)β | 2 (0.2) |
| AST | ||||
| >3 – 5 × ULN | 1 (0.7) | 7 (1.1) | - | 8 (0.9) |
| >5 – 20 × ULN | - | 1 (0.2)β | 1 (1.8)β | 2 (0.2) |