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Corresponding author. Address: CRC “AM e A Migliavacca” Center for Liver Diseases, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Via Francesco Sforza 35, 20122 Milan, Italy.
CRC A.M. e A. Migliavacca Center for Liver Diseases, Gastroenterology and Hepatology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
CRC A.M. e A. Migliavacca Center for Liver Diseases, Gastroenterology and Hepatology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
CRC A.M. e A. Migliavacca Center for Liver Diseases, Gastroenterology and Hepatology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
Glecaprevir/pibrentasvir combination has demonstrated excellent SVR rates (99.2%) in this real-world study in Italy.
•
Male gender (0.022) and HCV genotype 3 (0.046) were associated with the lowest rates of SVR after 8-week G/P treatment.
•
8.3% of the patients reported mild adverse events and 0.7% of them prematurely withdrew antiviral treatment.
Background and Aims
The efficacy and safety of glecaprevir/pibrentasvir (G/P) for patients infected with hepatitis C virus (HCV) have only been investigated in clinical trials, with no real-world data currently available. The aim of our study was to investigate the effectiveness and safety of G/P in a real-world setting.
Methods
All patients with HCV consecutively starting G/P between October 2017 and January 2018 within the NAVIGATORE-Lombardia Network were analyzed. G/P was administered according to drug label (8, 12 or 16 weeks). Fibrosis was staged either histologically or by liver stiffness measurement. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks after the end of treatment.
Results
A total of 723 patients (50% males) were treated with G/P, 89% for 8 weeks. The median age of our cohort was 58 years, with a median body mass index of 23.9 kg/m2, and median liver stiffness measurement of 6.1 kPa; 84% were F0-2 and 16% were interferon-experienced. Median HCV-RNA was 1,102,600 IU/ml, and 49% of patients had HCV genotype 1 (32% 1b), 28% genotype 2, 10% genotype 3 and 13% genotype 4. The median estimated glomerular filtration rate was 90.2 ml/min, platelet count 209x103/mm3 and albumin 4.3 g/dl. The SVR rates were 94% in intention-to-treat and 99.3% in per protocol analysis (8-week vs. 12 or 16-week: 99.2% vs. 100%). Five patients failed therapy because of post-treatment relapse; a post-treatment NS5A resistance-associated substitution was detected in 1 case. SVR rates were lower in males (p = 0.002) and in HCV genotype-3 (p = 0.046) patients treated for 8 weeks, but independent of treatment duration, fibrosis stage, baseline HCV-RNA, HIV co-infection, chronic kidney disease stage and viral kinetics. Mild adverse events were reported in 8.3% of the patients, and 0.7% of them prematurely withdrew treatment. Three patients died of drug-unrelated causes.
Conclusions
In a large real-world cohort of Italian patients, we confirmed the excellent effectiveness and safety of G/P administered for 8, 12 or 16 weeks.
Lay summary
A large number of patients with hepatitis C virus have been treated with glecaprevir/pibrentasvir (G/P) within the NAVIGATORE-Lombardia Network, in Italy. This is the first real-world study evaluating effectiveness and safety of G/P in patients with hepatitis C virus treated according to international recommendations. This study demonstrated excellent effectiveness (with sustained virological response rates of 99.3%) and safety profiles.
Chronic infection with hepatitis C virus (HCV) still remains a leading cause of morbidity and mortality worldwide, with more than 70 million individuals infected despite recent improvements in antiviral therapies.
In the last years, direct-acting antivirals (DAA) have dramatically revolutionized this scenario, since the availability of potent interferon (IFN)-free regimens has led to an increase in sustained virological response (SVR) rates, especially among patients in whom IFN-based antiviral therapies were previously contraindicated.
Moreover, because of the lack of tolerability issues, treatment indications have been widely extended to include patients with milder liver diseases, thus contributing to the goal of HCV eradication.
More recently, several efforts have been made to further simplify anti-HCV therapies in order to optimize treatment management and improve patient adherence. Glecaprevir/pibrentasvir (G/P) is a pangenotypic regimen recently approved for the treatment of chronic HCV infection. Glecaprevir is a non-structural (NS) protein 3/4 A protease inhibitor, which is co-formulated with the NS5A inhibitor pibrentasvir. In phase II and III registration trials, SVR rates >95% were achieved when this combination was administered for 8 to 16 weeks, without safety issues.
Glecaprevir plus Pibrantasvir for chronic hepatitis C virus genotype 1, 2, 4, 5 or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicenter phase 3 trial.
However, in clinical trials, restricted inclusion and exclusion criteria for the targeted patients may influence outcomes. In fact, patients who receive treatment in the real-world can differ from those enrolled in clinical trials due to older age, more advanced stages of fibrosis, and higher prevalence of co-morbidities and co-medications, all conditions potentially affecting SVR rates.
To assess the effectiveness and safety of the G/P combination in a real-world setting, we assessed both SVR rates as well as safety and tolerability data in a large cohort of Italian patients with HCV enrolled in a retrospective-longitudinal study.
Material and methods
This is a retrospective-longitudinal multicenter study evaluating the antiviral efficacy of the G/P combination in a real-world setting. Data were collected through the NAVIGATORE-Lombardia Network web-based platform, which is based on REDCap (Research Electronic Data Capture; http://project-redcap.org) and includes data from all DAA-treated patients starting from December 2014 in Lombardy, Northern Italy. All patients with HCV consecutively starting G/P between October 2017 and January 2018 were analyzed. Informed consent was obtained from each patient included in the study. The study protocol was approved by the Institutional Board of our Department (Ethical Committee Milan Area 2) and conforms to the ethical guidelines of the 1975 Declaration of Helsinki.
Assessments
Demographic, clinical and virological data were available throughout G/P administration and after the end of treatment (EOT). Below the lower limit of quantification (LLOQ), and according to HCV-RNA assays, HCV-RNA was defined unquantified but detected (<LLOQ) or not detected (ND). An EOT response was defined as HCV-RNA <LLOQ or ND at the time of treatment completion; a sustained virological response (SVR) was defined as <LLOQ or ND HCV-RNA 12 weeks after treatment completion.
Next generation sequencing was conducted on plasma samples collected from patients with a virological failure at baseline (when available), and the presence of polymorphisms in NS3 and NS5A was evaluated with the use of a 15% detection threshold. Substitutions (relative to baseline HCV sequence) that arose during treatment were analyzed.
Fibrosis stage was determined either histologically or non-invasively, by transient elastography (TE). According to the European Association for the Study of the Liver recommendations, advanced fibrosis was defined as METAVIR F3 or as a liver stiffness measurement (LSM) between 10 and 12.9 kPa. Cirrhosis was defined as METAVIR F4 or LSM ≥13 kPa.
These cut-offs were also endorsed by the Italian Medicines Agency (AIFA, Agenzia Italiana del Farmaco) to classify patients to be treated with any DAA regimen. In the NAVIGATORE-Lombardia platform, adverse events (AE) were also reported, at the discretion of treating physicians. Adherence to treatment was based on pharmacy refill data as well as on patients’ reports.
Study endpoints
The primary endpoint of the study was effectiveness of G/P regimen, i.e. rates of SVR at week 12 after treatment completion. Secondary endpoints of the study were: rates of treatment discontinuation due to drug-related adverse events and/or drug-related deaths; incidence of drug-related adverse events; rates of week 4 on-treatment response (HCV-RNA <LLOQ or undetectable 4 weeks after treatment start) and rates of EOT response (HCV-RNA <LLOQ or undetectable at EOT assessment)
Statistical analysis
Categorical variables were reported as frequencies (percentages) and continuous variables as median (range). Categorical variables were compared using the χ2 or the Fisher’s exact tests; continuous variables were compared using the Student’s t test, the Mann-Whitney U- test or the Kruskal-Wallis test, when appropriate. All tests were 2-sided and used a significance level of 0.05. Data handling and analysis were performed with Stat-View package (SAS Institute Inc., Cary, NC).
Results
Between 26 October 2017 and 31 January 2018, 723 HCV patients were treated with G/P in 32 centers in Lombardy. Three-hundred and sixty-one (50%) of them were males, with a median age of 58 (21–89) years. Baseline LSM was 6.1 (2.5–43) kPa; 601 (83%) patients had F0-F2 fibrosis, and 65 (9%) had F3 fibrosis. Cirrhosis had been previously diagnosed in 57 (8%) patients and was compensated (Child-Pugh A) in all cases. A total of 352 (49%) patients had HCV genotype 1, 203 (28%) had genotype 2, 74 (10%) had genotype 3 and 91 (13%) had genotype 4. Pre-treatment HCV-RNA was 1,063,109 (153–38,300,000) IU/ml. The median baseline creatinine value was 0.80 (0.46–10.0) mg/dl, with 18 (3%) patients having an eGFR below 30 ml/min/1.73 m2. One-hundred and sixteen (15%) patients were IFN-experienced, whilst no patients had failed any previous DAA-based regimen. Complete patient characteristics are provided (Table 1).
Table 1Baseline characteristics of the 723 patients included in the study.
Characteristics
All patients (n = 723)
8-week group (n = 639)
12,16-week group (n = 84§)
p value**
Age, years
58 (21–89)
58 (21–89)
60 (32–87)
0.04
Males
361 (50%)
310 (49%)
51 (61%)
0.03
BMI, kg/m2
24.0 (15.8–39.7)
23.7 (15.8–39.7)
24.6 (17.6–37.0)
0.19
IFN-experienced
106 (15%)
92 (14%)
13 (15%)
0.74
LSM, kPa
6.1 (2.5–43.0)
6.0 (2.5–19.8)
10.9 (2.7–43.0)
<0.0001
Fibrosis
<0.0001
F0–F2
601 (83%)
575 (90%)
26 (31%)
F3
65 (9%)
59 (9%)
6 (8%)
F4
57 (8%)
5 (1%)
52 (61%)
HCV genotype
<0.0001
1*
352 (49%)
321 (50%)
31 (37%)
2
203 (28%)
183 (29%)
20 (24%)
3
74 (10%)
53 (9%)
21 (25%)
4
91 (13%)
79 (12%)
12 (14%)
n.a.
3 (0)
3 (0)
0
HCV-RNA, IU/ml
1,063,109 (153–38,300,000)
1,055,046 (153–38,300,300)
1,092,837 (3,171–22,800,00)
0.59
ALT, U/L
50 (8–568)
49 (8–568)
63 (9–546)
0.02
PLT, 103/mm3
209 (25–691)
213 (46–691)
178 (25–367)
<0.0001
Albumin, g/dl
4.2 (2.3–5.9)
4.2 (2.3–5.9)
4.0 (2.9–5.7)
0.15
INR
1.0 (0.4–3.2)
1.00 (0.40–3.20)
1.03 (0.90–2.50)
0.71
Creatinine, mg/dl
0.80 (0.46–10.0)
0.80 (0.46–10.0)
0.87 (0.50–9.60)
0.05
CKD stage 4–5
18 (3%)
11 (2%)
7 (8%)
0.004
AH
172 (24%)
139 (22%)
33 (39%)
<0.0001
Diabetes
37 (5%)
23 (4%)
14 (17%)
<0.0001
Co–medications
311 (43%)
256 (40%)
55 (65%)
<0.0001
HIV/HBV
50 (7%)/3 (0.4%)
43 (7%)/3 (0.5%)
7 (8%)/0
0.83/1.00
AH, arterial hypertension; ALT, alanine aminotransferase; BMI, body mass index; CKD, chronic kidney disease; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IFN, interferon; INR, international normalized ratio; LSM, liver stiffness measurement; n.a., not available; nc, not classified; PLT, platelets 46).
Categorical variables were reported as frequencies (percentages) and continuous variables as median (range). Categorical variables were compared using the χ2 or the Fisher’s exact tests; continuous variables were compared using the Student’s t test, the Mann-Whitney U- test or the Kruskal-Wallis test, when appropriate.
Treatment duration was 8 weeks in 639 (88%), 12 weeks in 78 (11%) and 16 weeks in 6 (1%) patients. Patients treated with 8-week G/P were younger (p = 0.04), more frequently females (p = 0.03), with milder liver disease (p <0.0001), lower alanine aminotransferase (p = 0.002), platelet (p <0.0001) and creatinine (p = 0.05) values, and a lower prevalence of co-morbidities (p <0.0001) (Table 2). During treatment, 3 patients died of drug-unrelated causes (see below), and 35 (5%) were lost at follow-up; therefore, per protocol (PP) efficacy analysis has been carried out on 685 (95%) patients, treated for 8 (n = 605), 12 (n = 75) and 16 (n = 5) weeks.
Table 2Factors associated with week 4 and EOT virological responses.
Week 4 response (n = 502)
Non-week 4 response (n = 181)
p value
EOT response (n = 675)
Non-EOT response (n = 19)
p value
Age, years
58 (18–89)
58 (21–87)
0.37
58 (18–89)
59 (34–87)
0.72
Males
260 (52%)
85 (47%)
0.29
336 (50%)
8 (42%)
0.64
BMI, kg/m2
24.0 (17.3–38.9)
23.5 (16.8–39.7)
0.49
24.0 (16.8–39.7)
23.1 (18.7–26.9)
0.20
IFN-experienced
67 (13%)
35 (19%)
0.07
97 (14%)
4 (21%)
0.50
LSM, kPa
6.1 (2.8–43.0)
5.8 (2.5–27.0)
0.16
6.1 (2.8–43.0)
5.7 (4.1–9.7)
0.97
Fibrosis
0.19
0.74
F0–F2
423 (84%)
149 (82%)
557 (83%)
19 (100%)
F3
46 (9%)
13 (7%)
64 (10%)
0
F4
33 (7%)
19 (11%)
51 (7%)
0
HCV genotype*
<0.0001
0.62
1
247 (49%)#
87 (48%)°
326 (49%)§
11 (58%)^
2
152 (30%)
38 (21%)
191 (28%)
4 (21%)
3
52 (11%)
15 (8%)
66 (10%)
0
4
48 (10%)
41 (23%)
86 (13%)
4 (21%)
HCV-RNA, IU/ml
879,655 (324–22,800,000)
1,076,727 (5,726–38,300,000)
<0.0001
1,076,727 (153–38,300,000)
684,870 (43,445–8,730,379)
0.86
ALT, U/L
45 (29–76)
54 (9–215)
0.56
50 (8–568)
40 (23–201)
0.50
PLT, 103/mm3
209 (25–333)
207 (60–812)
0.46
207 (25–812)
208 (151–262)
0.81
Albumin, g/dl
4.2 (2.3–5.2)
4.3 (2.9–5.2)
0.55
4.2 (2.3–5.9)
4.3 (3.7–4.7)
0.90
INR
1.00 (0.40–3.16)
1.00 (0.80–2.46)
0.84
1.00 (0.40–3.16)
0.98 (0.88–1.50)
0.07
Creatinine, mg/dl
0.82 (0.46–10.00)
0.80 (0.49–8.60)
0.35
0.80 (0.46–9.60)
0.91 (0.59–4.99)
0.37
CKD stage 4–5
14 (3%)
4 (2%)
0.79
17 (3%)
1 (5%)
0.40
AH
114 (23%)
43 (25%)
0.84
158 (24%)
7 (37%)
0.18
Diabetes
23 (5%)
10 (6%)
0.69
33 (5%)
1 (5%)
1.00
Co–medications
211 (42%)
81 (85%)
0.54
291 (43%)
9 (47%)
0.82
HIV
35 (8%)
11 (6%)
0.73
48 (7%)
2 (11%)
0.64
Treatment duration
0.15
1.00
8-week
451 (89%)
154 (85%)
600 (89%)
17 (89%)
12-week
48 (10%)
24 (13%)
70 (10%)
2 (11%)
16-week
3 (1%)
3 (2%)
5 (1%)
0
Week-4 response
–
–
–
489 (72%)
0
<0.0001
AH, arterial hypertension; ALT, alanine aminotransferase; BMI, body mass index; CKD, chronic kidney disease; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IFN, interferon; INR, international normalized ratio; LSM, liver stiffness measurement; n.a., not available; PLT, platelets.
Categorical variables were reported as frequencies (percentages) and continuous variables as median (range). Categorical variables were compared using the χ2 or the Fisher’s exact tests; continuous variables were compared using the Student’s t test, the Mann-Whitney U- test or the Kruskal-Wallis test, when appropriate.
*HCV genotype available in 681 (99.7%) patients with week 4 response assessment and in 691 (99.6%) patients with EOT assessment. #1a in 76, 1b in 168, nc in 3. °1a in 31, 1b in 54, nc in 2. §1a in 101, 1b in 222, nc in 5. ^1a in 7, 1b in 4.
Overall, 502/683 (73%) patients achieved an on-treatment virological response at week 4, independently of treatment duration (8-week vs. 12 or 16-week: 75% vs. 65%, p = 1.00) (Fig. 1). Among them, HCV-RNA was <LLOQ in 175 (26%) and undetectable in 327 (48%). In patients with detectable HCV-RNA, median values were 27 (12–349) IU/ml. A higher baseline HCV-RNA was associated with a lack of week 4 on-treatment response (p = 0.0002) (Table 2).
Fig. 1Rates of virological response with G/P treatment. Rates of on-treatment (week 4 and EOT) and off-treatment (SVR) virological response overall, and according to G/P treatment schedule (PP analysis). Note: values are expressed as frequencies (%) and the 95% CI has been calculated. Categorical variables have been compared using the χ2 or the Fisher’s exact tests. EOT, end of treatment; G/P, glecaprevir/pibrentasvir; PP, per protocol; SVR, sustained virological response.
An EOT response was achieved by 675/694 (97%) patients, without differences between patients treated for 8 weeks vs. 12 or 16 weeks (97% vs. 97%, p = 1.00) (Fig. 1). Overall, HCV-RNA was <LLOQ in 105 (15%) and undetectable in 570 (82%) of them. In patients who tested positive at EOT, median HCV-RNA value was 19 (12–43) IU/ml. The achievement of a week 4 on-treatment response was the only factor associated with an EOT response (p <0.0001), whilst no baseline predictors were identified (Table 2).
Overall, an SVR was achieved by 680 patients, with corresponding SVR rates of 94% (95% CI 92%–96%) at intention-to-treat (ITT) and 99.3% (95% CI 98.6%–99.9%) at PP analysis, respectively (Fig. 1). At PP analysis, SVR rates were lower in males (males vs. females; 98.5% [95% CI 97.1%–99.8%] vs. 100%; p = 0.027), but independent of treatment duration (8-week vs. 12 or 16-week; 99.2% [95% CI 98.5%–99.9%] vs. 100%; p = 1.00), HCV genotype (3 vs. non-3; 97.1% [95% CI 92.9%–100%] vs. 99.5% [95% CI– 98.9%–100%]; p = 0.08), fibrosis stage (F0-F2 vs. F3-F4; 99.1% [95% CI 98.3%–99.9%] vs. 100%; p = 1.00], baseline HCV-RNA (<800,000 IU/ml vs. 800,000–6,000,000 IU/ml vs. >6,000,000 IU/ml; 99.6% [95% CI: 98.8%–99.9%] vs. 99.2% [95% CI: 97.9%–100%] vs. 98.4% [95% CI: 94.5%–100%]; p = 0.55), body mass index (BMI) (<30 vs. ≥30 kg/m2; 99.1% [95% CI: 98.1%–100%] vs. 100%; p = 1.00] or CKD stage (1–3 vs. 4,5; 99.1% [95% CI 98.3%–99.9%] vs. 100%, p = 1.00) (Fig. 1, Fig. 2). Moreover, SVR rates were not influenced by centers patients’ capability (≥30 vs. <30 patients; 99.2% [95% CI 98.3%–99.9%] vs. 99.5% [95% CI: 98.6%–100%]; p = 1.00) or on-treatment viral kinetics, being similar in patients with or without a virological response at both week 4 (yes vs. no; 99.2% [95% CI 98.3%–99.9%] vs. 99.4% [95% CI 98.3%–100%]; p = 1.00) and EOT [yes vs. no: 99.2% [95% CI 98.6%–99.9%] vs. 100%; p = 1.00) (Fig. 2). In patients treated with 8-weeks of G/P, both male gender (p = 0.022) and infection with HCV genotype 3 (p = 0.046) were independent predictors of treatment failure (Fig. 3, Table 3).
Fig. 2Rates of SVR according to the most important features in 685 patients with HCV treated with any duration of G/P (PP analysis). Note: values are expressed as frequencies (%) and the 95% CI has been calculated. Categorical variables have been compared using the χ2 or the Fisher’s exact tests. G/P, glecaprevir/pibrentasvir; HCV, hepatitis C virus; PP, per protocol; SVR, sustained virological response.
Fig. 3Rates of SVR according to the most important features in 600 patients with HCV treated with 8-week G/P (PP analysis). Note: values are expressed as frequencies (%) and the 95% CI has been calculated. Categorical variables have been compared using the χ2 or the Fisher’s exact tests. G/P, glecaprevir/pibrentasvir; HCV, hepatitis C virus; PP, per protocol; SVR, sustained virological response.
Table 3Per protocol analysis of clinical factors associated with an SVR following 8-week G/P.
SVR (n = 600)
Non-SVR (n = 5)
p value
Age, years
58 (18–89)
56 (27–72)
0.53
Age >65 years
206 (34)
2 (60%)
1.00
Males
280 (47%)
5 (100%)
0.02
BMI*, kg/m2
23.7 (15.8–39.7)
24.7 (23.4–25.9)
0.41
BMI* >30 kg/m2
28 (5%)
0
1.00
IFN-experienced
84 (14%)
0
1.00
LSM, kPa
5.9 (2.5–19.8)
6.3 (4.6–9.6)
0.99
Fibrosis Stage
F3
54 (9%)
0
1.00
F3–F4
4 (0.6%)
0
1.00
HCV genotype**
0.02
1
307 (51%)
0
2
173 (29%)
3 (60%)
3
46 (8%)
2 (40%)
4
71 (12%)
0
HCV genotype 3
46 (8%)
2 (40%)
0.047
HCV-RNA***, IU/ml
1,077,364 (153–38,300,000)
3,600,000 (193,662–8,722,885)
0.18
Baseline HCV-RNA***, IU/ml
≥800,000
315 (57%)
4 (80%)
0.40
≥6,000,000
54 (10%)
1 (20%)
0.41
ALT, U/L
49 (8–568)
39 (17–188)
0.94
PLT, 103/mm3
214 (46–812)
196 (127–349)
0.37
Albumin, g/dl
4.3 (2.7–5.9)
4.3 (4.1–4.5)
0.72
INR
1.00 (0.40–3.16)
1.00 (1.00–1.20)
0.28
Creatinine, mg/dl
0.80 (0.46–8.60)
0.98 (0.70–1.20)
0.24
eGFR**** ml/min/1.73 m2
83 (4–221)
84 (60–119)
0.82
CKD**** stage
<60 ml/min/1.73 m2
58 (12%)
0
1.00
<30 ml/min/1.73 m2
10 (2%)
0
1.00
AH °
135 (43%)
0
0.08
Diabetes
22 (7%)
0
1.00
Concomitant medications°°°
247 (56%)
0
0.02
Detectable HCV-RNA
Week 4 §
149 (26%)
1 (20%)
1.00
EOT§§
17 (3%)
0
1.00
BMI, body mass index; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; EOT, end of treatment; HCV, hepatitis C virus; IFN, interferon; INR, international normalized ratio; LSM, liver stiffness measurement; PLT, platelets; SVR, sustained virological response.
Numbers are expressed as n (%).
Categorical variables were reported as frequencies (percentages) and continuous variables as median (range). Categorical variables were compared using the χ2 or the Fisher’s exact tests; continuous variables were compared using the Student’s t test, the Mann-Whitney U- test or the Kruskal-Wallis test, when appropriate.
*BMI available in 341; **HCV genotype available in 602; ***HCV-RNA available in 557; ****eGFR/CKD available in 497; °AH data available in 132; °°Diabetes data available in 313. °°°Concomitant medication data available in 443; §Week 4 assessment available in 567; §§EOT assessment available in 586.
Overall, 5 (0.7%) patients had a virological relapse, 1 at week 4 and at week 12 of follow-up; 1 patient who did not attend the week 4 post-treatment visit tested positive 12 weeks after treatment completion (Table 4). They were all males, non-cirrhotic, treatment-naïve, infected with genotype 2 (3 patients) or 3 (2 patients) and without co-morbidities. In all cases, HCV genotype was retested at the time of relapse, and did not differ from that assessed before treatment. Resistance-associated substitutions (RASs) were found at the time of virological relapse in the patient infected with HCV genotype 3 (Y93H and L31I), but not in those infected with HCV genotype 2.
Table 4Clinical and virological characteristics of patients with post-treatment relapse.
Patient #1
Patient #2
Patient #3
Patient #4
Patient #5
Age, years
69
72
51
56
27
Gender
male
male
male
male
male
BMI, kg/m2
25.0
23.4
23.6
25.9
24.7
HCV genotype
2
2
3a
3
2c
HBV/HIV co–infection
no
no
no
no
no
LSM, kPa
6.4
6.3
4.6
9.6
4.8
eGFR, ml/min/mm3
60
75
119
100
84
Treatment history
naive
naive
naive
naive
naïve
G/P duration, weeks
8
8
8
8
8
Adherence
excellent
excellent
excellent
excellent
probably suboptimal
HCV-RNA, IU/ml
Baseline
8,722,885
1,310,660
193,662
3,600,000
4,730,000
Week 4
<12
undetected
undetected
undetected
17
EOT
undetected
undetected
undetected
undetected
<12
SVR4
<12
n.a.
237,605
undetected
<12
SVR12
773,839
1,259,750
297,879
24,500,000
862,650
RAS
NS3 variants
Baseline
n.a.
n.a.
none
n.a.
n.a.
At relapse
none
none
none
none
none
NS5A variants
Baseline
n.a.
n.a.
Y93H
n.a.
n.a.
At relapse
none
none
Y93H, L31I
none
none
BMI, body mass index; eGFR: estimated glomerular filtration rate; G/P, glecaprevir/pibrentasvir; HCV, hepatitis C virus; LSM, liver stiffness measurement; n.a., not available; RAS, resistance-associated substitutions; NS, non-structural.
Overall, compliance to the G/P label was excellent across all centers. Only 10 (1.4%) patients were undertreated, being treated for only 8 weeks despite the presence of cirrhosis (2 genotype 1a, 2 genotype 2, 1 genotype 4) or previous failure of a genotype 3 infection (4 F1, 1 F3). Nine of them achieved an SVR, with 1 F4 patient lost to follow-up, after the EOT.
Thirty-one (4.3%) patients underwent longer than recommended treatment. Thirty (4.2%) non-cirrhotic patients were treated for 12 weeks. Fibrosis stage was F0 in 3 patients, F1 in 13, F2 in 8 and F3 in 6; all F3 patients had an LSM below 12 kPa and normal platelet count. Among those patients there were 7 genotype 3, non-cirrhotic (F1 in 1, F2 in 5 and F3 in 1), treatment-naïve patients. All these patients achieved an SVR. In addition, G/P was successfully administered for 16 weeks to a single naïve cirrhotic patient with genotype 3 infection, who had developed both hepatocellular carcinoma and variceal bleeding prior to DAA start.
Safety and tolerability
Sixty (8.3%) patients reported at least 1 adverse event, which was considered by physicians to be treatment-related. Among them, pruritus (2.5%), fatigue (2%), nausea (1.5%) and headache (1.0%) were the most frequently reported. Four (0.5%) patients had to discontinue G/P due to an AE (nausea in 2, pruritus in 1 and jaundice [total bilirubin 12 mg/dl] in 1): all of them were infected with genotype 2 and 3 of them were cirrhotic. Median time to discontinuation was 8 (5–8) weeks, despite that, all achieved an SVR. The single patient who prematurely withdrew antiviral therapy at week-8 (vs. week-12) due to poor adherence, also achieved an SVR. Three (0.4%) patients (F4 in 2, F1 in 1) died due to treatment unrelated causes (cerebral stroke, septic shock and disseminated intravascular coagulation) before the EOT (Table 5).
Table 5Prevalence of AE according to G/P treatment schedule.
Categorical variables were reported as frequencies (percentages) and were compared using the χ2 or the Fisher’s exact tests.
*Both patients with poorly controlled arterial hypertension at baseline. **Nausea (n = 2), pruritus (n = 1), jaundice (n = 1). ***DIC, cerebral stroke, septic shock (not drug-related). No patients in the 16-week group reported any AE. Values are expressed as n (%).
This is the first real-world study demonstrating excellent SVR rates in a large real-world cohort of patients with HCV treated with G/P for 8 to 16 weeks. So far, only data from registration trials were available, reporting SVR rates ≥95% in selected HCV-infected patients treated with the G/P combination.
Glecaprevir plus Pibrantasvir for chronic hepatitis C virus genotype 1, 2, 4, 5 or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicenter phase 3 trial.
Indeed, after G/P EMA approval in July 2017, Italy was among the first countries in Europe to have G/P commercially available for the treatment of chronic HCV infection.
In our study, 723 patients were consecutively treated with G/P in 32 centers in Lombardy, and mostly underwent the shorter 8-week treatment duration. As per drug label, and according to international recommendations,
8-week G/P is indicated for the treatment of any non-cirrhotic patients without genotype 3 infection, and for treatment-naïve non-cirrhotic genotype 3 patients. Therefore, the large number of patients treated with the shorter G/P duration in our cohort was not unexpected, since in Italy the majority of cirrhotics had already been treated during the first period after DAA approval (December 2014), as defined by former AIFA reimbursement rules.
Not surprisingly, demographic and clinical features of those patients significantly differed from those displayed by patients undergoing longer treatment duration. In fact, the former displayed features commonly associated with milder stages of fibrosis, such as younger age, low prevalence of genotype 3 infection as well as of other co-morbidities. Not unexpectedly, they were quite similar to those showed by patients included in registration trials according to HCV genotype.
In our cohort, we obtained overall excellent SVR rates (99.3%) across all genotypes, since only 5 patients (3 genotype 2 and 2 genotype 3) failed to achieve viral eradication because of post-treatment virological relapse. These high SVR rates are in line with those reported in registration trials, ranging between 95% and 100%.
Glecaprevir plus Pibrantasvir for chronic hepatitis C virus genotype 1, 2, 4, 5 or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicenter phase 3 trial.
In contrast to the data reported in registration trials, we observed lower SVR rates among males, both in the overall population (p = 0.027) and in the 8-week treatment group (p = 0.022). Not surprisingly, in this latter subgroup of patients, genotype 3 was associated with the lowest chances (96%) of achieving an SVR (p = 0.046), whilst the other genotypes did not impact on treatment outcome. Whether these results reflect the lower effectiveness of G/P in these specific subgroups of patients requires further investigation, due to the overall very high SVR rates obtained in our study. Meanwhile, our results mirror those reported in trials including non-cirrhotic patients treated for 8 weeks, where at PP analysis this treatment schedule led to SVR rates of 100% in genotype 1 and 4,
patients. Also, in these studies relapses accounted for most of the treatment failures observed among genotype 2 and 3 patients. However, unlike what we observed in our study, all those patients had failed a previous course of antiviral therapy, displayed high baseline viral load (≥6 log10) as well as RAS emergence at failure assessment. In our study, the 5 patients who failed G/P did not show any of the clinical features usually associated with a poor treatment outcome, which was surprising, and adherence was not an issue. An emergent NS5A-associated RAS (L31I) was detected in only 1 case. However, it has never been associated with failure on G/P treatment or other DAA regimens.
In our study, only a restricted subgroup of patients underwent 12 or 16 weeks of G/P, with overall SVR rates of 100%. Again, these data are in line with those reported in phase III trials. In fact, in the EXPEDITION-1 study, all cirrhotics but 1 with HCV genotype 1a achieved an SVR.
Glecaprevir plus Pibrantasvir for chronic hepatitis C virus genotype 1, 2, 4, 5 or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicenter phase 3 trial.
In the same study, genotype 3 patients who had previously failed on the combination of pegylated-interferon ± ribavirin ± sofosbuvir achieved SVR rates of 95% (non-cirrhotics) and 96% (cirrhotics) when treated with 16 weeks of G/P.
Interestingly, even in the relatively limited subgroup of patients carrying clinical features usually associated with lower chances of achieving an SVR (i.e. infection with genotype 1a and 3 with advanced fibrosis, high HCV-RNA, high BMI) G/P treatment resulted in optimal effectiveness.
We found that SVR rates were independent of either baseline HCV viral load or on-treatment viral kinetics in all treatment duration groups. Indeed, although in our study baseline viral load influenced on-treatment viral kinetics (i.e. high on-treatment week 4 responses in low baseline HCV-RNA and high EOT rates in patients with faster viremia decline), we found that SVR rates were independent of these parameters. Unexpectedly, some patients (2.5%) were still viremic at the time of EOT assessment, independently of baseline HCV-RNA (p = 0.86) and treatment duration (p = 1.00). Interestingly, all of them achieved an SVR. Similar results were observed in the larger subgroup of patients (15%) where HCV-RNA was detected but <LLOQ. This is in line with what emerged from a recently presented pooled analysis of phase II and III clinical studies, including non-cirrhotic patients treated with 8-week G/P, which reported 100% SVR rates among 36/942 (4%) patients with HCV-RNA LLOQ at treatment week 4.
Similarly, no baseline clinical factors emerged as predictors of treatment failure from a recent integrated efficacy analysis of 2,041 patients with genotype 1–6 infections without cirrhosis treated for either 8 or 12 weeks with G/P.
In our study compliance to G/P label was very high across all network centers. In particular, the rate of under-treatment was very low (1.4%), and all patients treated with an off-label shortened treatment duration achieved an SVR at PP analysis. Moreover, the additional 4 patients who prematurely discontinued G/P for tolerability or safety reasons remained HCV-RNA undetectable after treatment withdrawal. Meanwhile, patients over-treated for up to 12 or 16 weeks eventually achieved an SVR. As expected based on the real-world setting and multicenter design of the study, some patients were lost to follow-up. However, they accounted for a very limited subgroup of patients and data lost did not significantly modify study results.
Although safety was not the primary endpoint of this study, since safety data collection was not among the main objectives of the NAVIGATORE-Lombardia web-based platform, we were able to obtain some meaningful information. Indeed, in our real-world study, the rates of AE were extremely low, and most of them were of mild intensity, with safety and tolerability profiles quite similar to those reported in registration trials.
The most frequently reported events were fatigue, nausea and pruritus, without differences between treatment durations. Four patients reported moderate to severe AEs (pruritus, nausea and jaundice) which finally led to G/P discontinuation, and 1 poorly compliant patient prematurely discontinued antiviral treatment. No treatment-related deaths were observed.
We acknowledge that our study suffers from some limitation strictly related to its real-world design. First of all, some clinical information might have been under-reported. Indeed, the prevalence of co-morbidities, co-medications and mild AEs, for example, have been likely underestimated if compared with the available national epidemiological data.
However, we strongly believe that all severe AEs (either related or not to G/P administration) have been carefully recorded by the treating centers. Secondly, despite the real-world setting, in our study the number of F3 patients was quite limited, since they had been mostly treated during the first months after DAA approval, as well as cirrhotics, according to former AIFA reimbursement rules.
Similarly, on-treatment viral kinetic data are not available for all patients included in the study, due to changes in mandatory on-treatment testing required by AIFA. Lastly, patients’ loss at follow-up is not unexpected in a real-world setting, however their very limited number should not significantly affect our study conclusions. We rather believe that these intrinsic limitations are fully counterbalanced by some peculiar strengths of the study: indeed, the strict AIFA reimbursement criteria have generally granted for a homogeneous characterization of HCV patients eligible for antiviral treatment, thus limiting the interpretation bias related to the multicenter design of the study. Moreover, all patients had been consecutively enrolled in the NAVIGATORE-Lombardia web-based platform, thus further limiting any other selection bias. Finally, although we occasionally faced a few deviations from G/P label and international recommendations this aspect further reinforces our study results, with particular reference to G/P antiviral potency.
In conclusion, we demonstrated for the first time the excellent effectiveness and safety of the G/P combination in a large cohort of patients with HCV treated in an Italian real-world setting.
Financial support
Unrestricted grant for NAVIGATORE-Lombardia web-based platform (AbbVie, Gilead, MSD)
Conflict of interest
Roberta D’Ambrosio: Speaker: AbbVie, Gilead, MSD; Advisory Board: AbbVie, Gilead; Research Grants: Gilead; Luisa Pasulo: Advisory Board: AbbVie; Massimo Puoti: Speaker’s bureau and Advisory: AbbVie, BMS, Boehringer Ingelheim, Janssen, Gilead, MSD, Roche; Reasearch Grant: Gilead, MSD; Maria Vinci: Advisory Board: AbbVie; Grant: AbbVie; Alessandro Soria: Consultation fees: AbbVie; Alessio Michele Aghemo: Speaker’s bureau and Advisory: AbbVie, Gilead, Janssen, MSD; Maria Grazia Rumi: Speaker: AbbVie, Gilead, MSD; Advisory Board: AbbVie; Lorenzo Morini: Speaker: AbbVie; Alessia Giorgini: Speaker: AbbVie, MSD, Gilead; Advisory Board: AbbVie; Paolo Del Poggio: Speaker: MSD; Caterina Uberti-Foppa: Consultation fees: AbbVie, MSD; Paolo Bonfanti: Speaker: MSD, Gilead; Advisory Board MSD, Gilead; Natalia Terreni: Advisory Board: AbbVie; Andrea Gori: Consultation fees, Speaker’s bureau, Research Grants: AbbVie, Astellas, BMS, Boehringer Ingelheim, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Viiv; Pietro Lampertico: Speaker’s bureau and Advisory: AbbVie, BMS, Gilead, GSK, Janssen, MSD, Roche; Stefano Fagiuoli: Speaker’s bureau and Advisory for AbbVie, Bayer, Gilead, MSD, Kedrion, Novartis. All other authors have nothing to disclose.
Please refer to the accompanying ICMJE disclosure forms for further details.
Authors’ contributions
Concept and design: Roberta D’Ambrosio, Pietro Lampertico, Stefano Fagiuoli. Data collection: Roberta D’Ambrosio, Luisa Pasulo, Massimo Puoti, Maria Vinci, Monica Schiavini, Sergio Lazzaroni, Alessandro Soria, Federico Gatti, Barbara Menzaghi, Alessio Michele Aghemo, Francesca Capelli, Maria Grazia Rumi, Lorenzo Morini, Alessia Giorgini, Maria Graciella Pigozzi, Angelo Rossini, Franco Maggiolo, Angelo Pan, Massimo Memoli, Ombretta Spinelli, Paolo Del Poggio, Valeria Saladino, Angiola Spinetti, Anna De Bona, Andrea Capretti, Caterina Uberti-Foppa, Paolo Bonfanti, Natalia Terreni, Fernanda Menozzi, Alberto Eraldo Colombo, Omar Giglio, Riccardo Centenaro, Simona Landonio, Andrea Gori, Paolo Viganò. Writing of article: Roberta D’Ambrosio, Massimo Puoti, Pietro Lampertico. Statistical analysis: Roberta D’Ambrosio, Pietro Lampertico. Data management: Marta Borghi, Viviana Picciotto, Franco Noventa. Virological analysis: Stefania Paolucci. Critical revision of the manuscript: Massimo Puoti, Alessio Aghemo, Pietro Lampertico, Stefano Fagiuoli
Acknowledgements
The authors thank Dr Elisabetta Degasperi (Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan) for her clinical support and Giuliano Rizzardini (ASST Sacco, Milan) for his critical review of the manuscript. They also thank Roberta Soffredini (Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan), Sara Gritti (FROM, Bergamo) and Pietro Giani (FROM, Bergamo) for data handling, and Ms Roberta Ferrari (Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan) for secretarial assistance.
The NAVIGATORE-Lombardia Network – Appendix
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Gastroenterology and Hepatology, Università degli Studi di Milano, Milan: Roberta D’Ambrosio, Elisabetta Degasperi, Marta Borghi, Roberta Soffredini, Riccardo Perbellini, Pietro Lampertico; Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Infectious Diseases: Andrea Gori, Valentina Ferroni; ASST Papa Giovanni XXIII, Bergamo, Gastroenterology: Luisa Pasulo, Maria Colpani Matteo Manini, Stefano Fagiuoli; ASST Papa Giovanni XXIII, Bergamo, Infectious Disease: Franco Maggiolo, Giuliana Cologni; “M.O.A. Locatelli” Hospital, Piario (BG): Sergio Lazzaroni; Policlinico San Marco, Zingonia (BG): Paolo Del Poggio; ASST Grande Ospedale Metropolitano Niguarda, Milan, Gastroenterology and Hepatology: Maria Vinci, Stella De Nicola, Chiara Mazzarelli, Teresa Angelini Zucchetti, Viviana Picciotto; ASST Grande Ospedale Metropolitano Niguarda, Milan, Infectious Disesases: Massimo Puoti, Chiara Baiguera, Roberto Rossotti; ASST Sacco, Milan, Infectious Diseases: Monica Schiavini, Simona Landonio, Carlo Federico Magni, Giuliano Rizzardini; San Gerardo Hospital, ASST Monza, Infectious Diseases, Alessandro Soria, Alessandra Gambaro, Anna Spolti, Nunzia Bottalico; ASST Ovest Milanese, Legnano (MI), Infectious Diseases: Carlo Magnani, Paolo Viganò, Maurizio Mena, Massimo Villa, Ilaria Caramma, Cristina Basilico, Tiziana Re; ASST Ovest Milanese, Legnano (MI), Internal Medicine: Capelli Francesca, Sara Biagiotti, Antonino Mazzone; ASST Ovest Milanese, Legnano (MI), Gastroenterology: Valeria Saladino, Maria Pia Baldacci; ASST Ovest Milanese, Legnano (MI), Hospital Pharmacy: Federico Gatti, Luca Varalli; ASST Ovest Milanese, Abbiategrasso (MI), Internal Medicine: Lorenzo Morini; Busto Arsizio Hospital, ASST Valle Olona, Varese, Infectious Disease: Barbara Menzaghi, Maddalena Farinazzo; Humanitas Research Hospital, Humanitas University, Pieve Emanuele (MI), Internal Medicine and Hepatology: Alessio Aghemo, Ana Lleo, Vincenzo Boccaccio, Alberto Gatti Comini; San Giuseppe Hospital, Università degli Studi di Milano, Milan, Hepatology: Maria Grazia Rumi, Ilaria Fanetti; AAST Santi Paolo e Carlo, Milan, Internal Medicine: Alessia Giorgini, Clara Di Benedetto (MD), Daniel Orellana, Paola Zermiani, Massimo Zuin; AAST Santi Paolo e Carlo, Milan, Infectious Diseases: Anna De Bona, Antonella D’Arminio Monforte; AAST Santi Paolo e Carlo, Milan, Gastroenterology: Andrea Capretti, Maria Teresa Taddei, Marco Soncini; Spedali Civili Hospital, ASST Brescia, Infectious Diseases: Angiola Spinetti, Stefania Zaltron; Spedali Civili Hospital, ASST Brescia, Gastroenterology: Marie Graciella Pigozzi; Spedali Civili Hospital, ASST Brescia, Hepatology: Angelo Rossini; ASST Cremona, Cremona: Angelo Pan, Fabio Zacchi, Alessia Zoncada, Paola Brambilla; San Raffaele Hospital, Milan; Internal Medicine: Massimo Memoli; San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Immunology and Infectious Diseases: Caterina Uberti-Foppa, Stefania Salpietro, Hasson Hamid, Emanuela Messina; ASST Lariana, Como; Internal Medicine, Cantù (CO): Ombretta Spinelli; ASST Lariana, Como; Internal Medicine, Como: Alberto Eraldo Colombo; Infectious Diseases, Como: Omar Giglio; ASST Lecco, Lecco, Infectious Diseases: Paolo Bonfanti, Chiara Molteni; Valduce Hospital, Como: Natalia Terreni, Giancarlo Spinzi, Simone Conforti, Elisabetta Clerici; ASST Crema, Crema (CR), Gastroenterology: Fernanda Menozzi, Elisabetta Buscarini; Vizzolo Predabissi Hospital, Vizzolo Predabissi (MI): Riccardo Centenaro, Ada Corbellini; QUOVADIS no profit Association: Franco Noventa; Fondazione Ricerca Ospedale Maggiore (FROM), Bergamo: Sara Gritti, Pietro Giani.
Supplementary data
The following are the Supplementary data to this article:
Glecaprevir plus Pibrantasvir for chronic hepatitis C virus genotype 1, 2, 4, 5 or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicenter phase 3 trial.
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