Virologic response
The SVR12 rates were 92% (47/51; 95% CI 81–98%) in each treatment group (Table
2). Both treatment groups met their primary efficacy endpoints with SVR12 rates that were statistically superior compared with the spontaneous clearance rate of 1% (
p < 0.001).
Table 2
Virologic response during and after treatment
HCV RNA < 15 IU/mL, n/n (%) |
On treatment | | |
Week 2 | 23/51 (45) | 26/51 (51) |
Week 4 | 49/51 (96) | 46/51 (90) |
Week 8 | 51/51 (100) | 49/51 (96) |
Week 12 | 51/51 (100) | 49/49 (100) |
After treatment | | |
Week 4 (SVR4) | 48/51 (94) | 49/51 (96) |
Week 12 (SVR12) | 47/51 (92) | 47/51 (92) |
95% CI | 81–98 | 81–98 |
Relapse after the end of treatment | 4 (8) | 2 (4) |
Discontinued treatment due to adverse events | 0 | 2 (4) |
When examined by genotype, SVR12 rates were high for patients with genotype 1 or 2 regardless if they received 12 weeks of sofosbuvir–velpatasvir or sofosbuvir–velpatasvir plus ribavirin (rates ranged from 89 to 100%, Table
3). The 1 patient with genotype 3 HCV infection in the study who was randomized to the sofosbuvir–velpatasvir group did not achieve SVR12. When examined by baseline CPT class, SVR12 rates were high in patients with CPT class B cirrhosis (≥ 95%) in both treatment groups (Table
3). Of the patients with baseline CPT class C cirrhosis, 80% (8/10) and 70% (7/10) in the sofosbuvir–velpatasvir and sofosbuvir–velpatasvir plus ribavirin groups, respectively, achieved SVR12.
Table 3
Rates of SVR12 by subgroup
Overall SVR12 | 47/51 (92) | 47/51 (92) |
Genotype | | |
1a | 0/1 (0) | – |
1b | 39/40 (98) | 35/39 (90) |
2 | 8/9 (89) | 12/12 (100)a |
3 | 0/1 (0) | – |
Baseline CPT class | | |
A | 1/1 (100) | 2/2 (100) |
B | 38/40 (95) | 38/39 (97) |
C | 8/10 (80) | 7/10 (70) |
A total of 8 patients did not achieve SVR12, with 6 patients experiencing virologic relapse (Supplemental Table 3). No patients had virologic non-response. In the sofosbuvir–velpatasvir group, 4 of 51 patients (8%) relapsed. In the sofosbuvir–velpatasvir plus ribavirin group, 4 of 51 patients (8%) did not achieve SVR12. Of these 4 patients, 2 relapsed and 2 discontinued treatment early due to AEs and subsequently died.
Analysis of resistance
Among the 100 patients included in the resistance analysis population, 41% (41/100) had baseline NS5A RASs. No patient had NS5B nucleoside inhibitor (NI) RASs.
In the sofosbuvir–velpatasvir group, 97% (33/34) of patients without baseline NS5A RASs and 82% (14/17) of patients with baseline NS5A RASs achieved SVR12. Of the 41 patients with genotype 1 HCV infection, there was 1 patient without baseline NS5A RASs and 1 patient with baseline NS5A RASs who relapsed. In the sofosbuvir–velpatasvir plus ribavirin group, 96% (24/25) of patients without baseline NS5A RASs and 96% (23/24) of patients with baseline NS5A RASs achieved SVR12. Of the 37 patients with genotype 1 HCV infection, there was 1 patient without baseline NS5A RASs and 1 patient with baseline NS5A RASs who relapsed.
Of the 6 patients who experienced virologic relapse across both treatment groups, 4 had treatment-emergent NS5A RASs. No patient in either treatment group had NS5B NI RASs detected at baseline or relapse.
Safety
More patients treated with sofosbuvir–velpatasvir plus ribavirin experienced AEs (86%, 44/51) compared with patients treated with sofosbuvir–velpatasvir (69%, 35/51) (Table
5). No consistent, clinically significant trends were observed when looking at AE rates by CPT class, nor by age group.
Table 5
Adverse events and grade 3 and 4 laboratory abnormalities
Number (%) of patients experiencing any |
Adverse event | 35 (69) | 44 (86) |
Grade 3 or above adverse event | 2 (4) | 5 (10) |
Serious adverse event | 4 (8) | 7 (14) |
Adverse event leading to discontinuation of sofosbuvir/velpatasvir | 0 | 2 (4) |
Adverse event leading to discontinuation of ribavirin | N/A | 9 (18) |
Adverse event leading to modification or interruption of ribavirin | N/A | 18 (35) |
Deaths | 0 | 3 (6) |
Common adverse events (≥ 10% either group) |
Anemia | 0 | 20 (39) |
Nasopharyngitis | 7 (14) | 3 (6) |
Diarrhea | 0 | 7 (14) |
Laboratory abnormalities (≥ 10% either group) |
Hemoglobin < 10 g/dL | 2 (4) | 7 (14) |
Lymphocytes, < 500/mm3 | 0 | 5 (10) |
Platelets, 25,000–50,000/mm3 | 1 (2) | 6 (12) |
Hyperglycemia, > 250–500 mg/dL | 5 (10) | 9 (18) |
Total bilirubin, > 2.5 × ULN | 6 (12) | 12 (24) |
Despite all the patients in the study having advanced liver disease, most AEs reported in this study were Grade 1 (mild) or Grade 2 (moderate) in severity. The most common AEs in the sofosbuvir–velpatasvir group were nasopharyngitis (14%) and in the sofosbuvir–velpatasvir plus ribavirin group they were anemia (39%) and diarrhea (14%).
Patients in the sofosbuvir–velpatasvir plus ribavirin group experienced AEs consistent with ribavirin toxicity. Eighteen of 51 patients (35%) had AEs that led to modification or interruption of ribavirin and 9 patients (18%) had AEs that led to discontinuation of ribavirin, with anemia being the most common in both instances.
Four patients (8%) in the sofosbuvir–velpatasvir group and 7 patients (14%) in the sofosbuvir–velpatasvir plus ribavirin group had serious adverse events (SAEs), and most were not considered treatment-related by the investigator (Supplemental Table 5). The only SAEs that occurred in > 1 patient were femur fracture (2 in the sofosbuvir–velpatasvir plus ribavirin group) and hepatic encephalopathy (1 in the sofosbuvir–velpatasvir group, 2 in the sofosbuvir–velpatasvir plus ribavirin group). Two of the three SAEs of hepatic encephalopathy occurred in patients with CPT class C cirrhosis.
Three patients in the study developed HCC, all of whom were diagnosed following treatment (on posttreatment day 1, posttreatment day 70 and posttreatment day 124). Two of the patients had CPT class B at baseline and one had CPT class C. The investigator did not consider these events related to study drug. There were 4 patients enrolled who had a history of HCC, none of whom experienced recurrence during the study.
Three deaths occurred during the study and all 3 patients received treatment with sofosbuvir–velpatasvir plus ribavirin. The ages of the patients who died were 51, 59 and 67 years; all 3 patients had CPT class C at baseline. Two of these patients discontinued study drugs early due to AEs not related to treatment. All 3 deaths occurred after treatment was stopped (posttreatment days 5 and 17 for the 2 patients that discontinued study drugs prematurely, and posttreatment day 158 for the patient that completed 12 weeks of study treatment). All of the deaths were due to progression of end-stage liver disease (septicemia, portal hypertension leading to gastrointestinal bleeding, and HCC) and none were considered to be related to study drugs by the investigator (Supplemental Table 6). No other patients discontinued sofosbuvir–velpatasvir in the study.
Fewer patients in the sofosbuvir–velpatasvir group had Grade 3 or 4 laboratory abnormalities compared with the sofosbuvir–velpatasvir plus ribavirin group (27 vs 53%, respectively) (Table
5). The observed laboratory abnormalities were consistent with those expected in a population with decompensated liver disease and, in the sofosbuvir–velpatasvir plus ribavirin group, consistent with the known toxicities of ribavirin. Post-baseline hemoglobin values < 10 g/dL were observed in 2 patients (4%) in the sofosbuvir–velpatasvir group and 7 patients (14%) in the sofosbuvir–velpatasvir plus ribavirin group. Additional information about laboratory abnormalities is provided in the supplementary information (Supplemental Fig. 2).