Date Published: May 15, 2019
Publisher: Public Library of Science
Author(s): Alessandra Mangia, Valeria Piazzolla, Anna Giannelli, Egidio Visaggi, Nicola Minerva, Vincenzo Palmieri, Immacolata Carraturo, Domenico Potenza, Nicola Napoli, Gianfranco Lauletta, Vincenzo Tagarielli, Rosanna Santoro, Ernesto Piccigallo, Sergio De Gioia, Angelo Chimenti, Giuseppe Cuccorese, Antonio Metrangolo, Michele Mazzola, Ernesto Agostinacchio, Giuseppe Mennea, Carlo Sabbà, Marina Cela, Massimiliano Copetti, Ruggiero Losappio, Tatsuo Kanda.
The pangenotypic single tablet regimen of NS5B inhibitor sofobuvir (SOF) and NS5A inhibitor velpatasvir (VEL) is advised for 12 weeks in HCV-infected patients including those with compensated cirrhosis. Addition of ribavirin (RBV) may be considered in genotype 3 (GT3) with compensated and is recommended in decompensated cirrhosis. Real-life results with SOF/VEL are limited. To evaluate efficacy and safety in a large real-world-cohort including patients with different GTs and various fibrosis stages.
In total, 1429 patients were treated with SOF/VEL 400/100 mg for 12 weeks in the Puglia registry between June 2017 and May 2018. 1319 (92.3%) reached week 12 post-treatment (SVR12) at the moment. Only 41 received RBV. Diagnosis of cirrhosis was based on transient elastography and/or APRI or FIB-4 scores. Sensitivity analysis in the population including all patients except non virological failure was conducted. Primary efficacy endpoint was the percentage of patients with SVR12.
Patients’ mean age was 63.8 years, 42.3% had GT1. The majority were naïve and 735 (55.5%) F0/F2. Of the remaining 587, 282 had cirrhosis. SVR12 was 98.5%, 98.0% in GT1, 99.4% in GT2, 97.1% in GT3, 100% in GT4. Overall, SVR12 by sensitivity analysis was 99.4%; 99.7% among F0-F1. Among 218 PWID, SVR12 was 94.5%. Discontinuation rates were 3.7% among PWID and 0.7% among non-PWID (p = 0.004).
SOF/VEL treatment of chronic HCV infection reaches very high cure rates in a variety of patients; including those with F0/F1 and PWID.
WHO guidelines aim at HCV elimination by 2030 . The eradication objective is attainable through simple antiviral regimens, associated with high efficacy and universal duration, and therefore able to facilitate treatment access. In HCV treatment, real-world data validate the effectiveness and safety for regimens previously approved based on small numbers of patients. SOF/VEL is a Single Tablet Regimen (STR) (400/100 mg) administered for 12 weeks regardless of GT . In phase III trials, this treatment demonstrates rates of SVR12 > 95% with excellent safety profile in patients with GT1-6 infection [3,4]. RBV addition is advised in GT3 cirrhotic and recommended in decompensated patients [5,6]. All other patients can be treated with a fixed 12-week regimen that does not require on treatment monitoring .
For the present study, all consecutive patients with chronic HCV infection who completed SOF/VEL treatment between June 2017 and May 2018 at the participating centres in Puglia were included. The study group involves 19 of 31 regional prescribing centres sharing an ongoing program on DAA treatment since 2015. Of 1429 patients treated, 1319 who have reached week 12 post-treatment are included in this real-world-cohort analysis. The individual patient treatment schedule was chosen at the discretion of treating physicians . In case of cirrhosis, GT3 infection or past treatment failure, RBV was administered when judged necessary. Patients who had failed SOF/RBV or SOF/NS3 inhibitor were included, patients with prior NS5A inhibitor therapy were excluded. With the exception of those with compensated cirrhosis and of PWID, patients were seen at baseline, week 4 on-treatment and week 12 post-treatment. Cirrhotic patients including decompensated and PWID received additional visits at week 8, at the end of treatment, and at 4 post-treatment. Demographic, clinical and virology parameters were assessed at each visit. Data were collected in an electronic database. Diagnosis of fibrosis stage was based on liver biopsy or on transient elastography (FibroScan, Echosens, Paris, France) (TE) results using the standard threshold of 12.5 KPa to define cirrhosis and 10.1 to define advanced fibrosis. Aspartate/platelets ratio index, APRI score and FIB-4 were available for every patient. A cut-off of >2, and >3.25 respectively were used to define cirrhosis .
The primary endpoint of this study was an undetectable HCV-RNA 12 weeks post-treatment (SVR12) assessed in he population including all patients except non-virological failure. Additional endpoints were adverse events rates (AEs) and treatment discontinuations due to AEs. SVR12, treatment emergent AEs and laboratory abnormalities were analyzed by fibrosis stage. Virological failure or relapse was defined as end of therapy undetectable HCV-RNA which became detectable again without proven re-infection.
SVR12 were analyzed in the whole population: all patients followed-up 12 weeks minimum, including patients who had treatment discontinuation for any reason or death during treatment or within 12 weeks of follow-up. A sensitivity analysis was conducted in the population including all patients except non virological failure. Patients who have not reached scheduled week 12 follow-up were not eligible for both analyses.
Of the 1319 patients, only 20 did not achieve SVR12. In the whole population 98.5% (95% CI: 97.6%-99.0%) attained SVR12 after SOF/VEL. Of 20 patients who did not achieve SVR12, 8 were relapsers, the remaining had early discontinuation of treatment (n = 7) or were lost to follow up (n = 5). Study disposition in Table 2. Four additional patients who discontinued early achieved SVR12. Of 16 who were not able to complete treatment, two patients discontinued after a single dose. Among the 8 relapsers, 2 were proven re-infected, therefore the real SVR12 rate in the overall cohort was 98.7%, 95% CI: 97.8%-99.1%). The addition of RBV did not improve SVR12 that was 92.7% (95% CI: 78.9%-98.0%) with, and 98.7% (95% CI: 97.8%-99.2%) without RBV (p = 0.02). SVR12 was 98.3% (95% CI: 96.7%-99.1%) in 587 patients with F3-F4 and 98.6% (95% CI: 97.4%-99.3%) in patients with stage F0-F2 (p = 0.65). Analysis by genotype showed SVR12 of 98.0% in GT1, 99.4% in GT2, 97.1% in GT3, 100% in GT4 (p = 0.12). SVR12 by baseline characteristics is reported in Fig 2. Of 204 patients with genotype 3 only 25 received ribavirin in addition to SOF/VEL. SVR12 was 96% (95% CI 77.6%-99.7%) in patients treated with and 97.2% (95% CI 93.6%-98.8%) in patients treated without ribavirin (p = 0.54).
Among patients with fibrosis stage F3-F4, in the whole population SVR12 was 98.3%. The rate is similar to that observed in 732 patients with stage F0-F2 (p = 0.65). Of 20 patients who did not achieve SVR12, 10 had F3-F4 and 10 had F0-F2. More detailed analysis of SVR12 by stage of fibrosis demonstrated that 334 of 335 F0-F1 patients achieved SVR12 (99.7%). The corresponding figures in patients with F2 stage of fibrosis were 388 of 397 (97.7%, 95% CI: 98.0%-99.9%) (p = 0.026) (Fig 2). Virological responders for F3 and F4 were 99.0% (95% CI: 96.9%-99.7%) and 97.5% (95% CI: 94.7%-98.9%), respectively (p = 0.20). Excluding two re-infections, in stage 3 and 1 respectively, only 18 subjects experienced a relapse.
Sensitivity analysis was performed on the entire cohort excluding patients who did not complete the assigned treatment for reasons not related to treatment. Overall, SVR12 was 99.1% (95% CI: 98.7%-99.7%). When patients with F0-F2 stage of fibrosis were analyzed, of the 10 non responders, 6 had discontinued treatment with a resulting SVR12 of 99.4% (95% CI: 98.4%-99.8%).
History of prior treatment might influence SVR12 rates. In this study, only 261 patients were treatment-experienced; of them 231 had failed Peg-IFN-based, 30 SOF-based regimens (including the combination with simeprevir or ribavirin). In the whole population, SVR12 rate among treatment failures was 98.5% (95% CI: 95.8%-99.5%), which was identical to that observed among naïve patients (p = 1.0); this suggests that with SOF/VEL a previous negative treatment result, including protease inhibitors failure is not anymore a negative predictor. When a subgroup analysis by stage of fibrosis and past treatment history was performed, within naive SVR12 rates (98.5%) were identical for F0-F2 and F3-F4. For experienced patients, 97.5% (95% CI: 92.4%-99.36%) SVR12 rate associated with F3/F4 stage was marginally lower than 98.5% (95% CI: 95.4%-99.9%) of patients with F0-F2 (p = 0.34).
Overall, 218 (16.5%, 95% CI 14.6–18.6) PWID patients were treated within this real-world-cohort. Of them, one with HCC moved to another Country and discontinued after the first dose. Overall, 40% were on OST, 60% on active drug use having injected drugs during the previous month (mostly heroin). Patients on OST were taking methadone (n = 69) or buprenorphine (n = 18). The vast majority of PWID (85.8%) were male. Male gender was significantly more common than in nonPWID (p = 0.0001). Over 95% of patients were younger than 66 years, this proportion was also significantly higher than in nonPWID (p<0.0001). Only 4 were HIV antibodies positive with undetectable virus on stable treatment for HIV. Within PWID 53.2% had F0-F2 stage of fibrosis as compared to 55.9% in nonPWID (p = 0.45). Of patients with CTP B7-9, 7 were PWID. The proportion of patients with GT3 was significantly higher than in general population (43%vs10.6%, p = 0.0001). Study disposition in PWID and nonPWID is reported in Table 3. Overall, 94.5% (95% CI: 90.3%-97.0%) of PWID achieved SVR12 as compared to 99.3% (95% CI: 98.5%-99.6%) among not PWID (p<0.0001). By sensitivity analysis, SVR12 rates rose to 97.6% (95% CI: 94.2%-99.9%) as of 12 patients who failed to achieve SVR12 in this subgroup, 4 were lost-to-follow-up and did not achieve end of treatment, 5 experienced a relapse,and 3 died. A wide range of concomitant diseases was present in this Real-Word HCV cohort and as shown in Table 2 only 14.4% of patients were not taking concomitant medications. As reported in Fig 3, 70% of patients taking concomitant medications received from 4 to 8 different drugs in association with SOF/VEL. All patients with a neoplastic disease received concomitant chemotherapy without any additional adverse event and were able to complete their oncologic schedule. Of 228 (15.3%) patients with blood hypertension 91% were receiving various antihypertensive medications including sartans, enalapril and amplodipine. Ivabradine and NAO (dabitagram, apixabam and clopidogrel) were well tolerated. Beta-blockers were used by 21 patients no side effects were reported. No patients on amiodarone were included. Two hundred and fifty four patients were taking lipid lowering agents; only those taking atorvastatin and rosuvastatin were discontinued for 12 weeks to be re-started after antiviral therapy. Treatment with simvastatin was continued at 20 mg. Moreover, 97 of 303 female patients in their active sexual life were taking oral contraceptives and carried on without any negative effect on SVR12 rates. Of 20 HBV infected patients, 11 were already on treatment with entecavir (n = 6) and tenofovir (n = 1) and had undetectable HBV-DNA levels. The patient on tenofovir showed no relevant kidney or bone metabolism change during follow-up. The remaining 7 patients had inactive HBV infection and mild liver disease. None of the 4 patients on concomitant HIV treatment, including protease, nucleotide reverse transcriptase and integrase inhibitors required any HAART modification. Among PWID, 35% of patients were taking different analgesic (10 olanzepine, 15 haloperidol and 21 ketamine). None of them experienced related toxicity. Additionally, 14 patients on alprazolam, 10 on diazepam, 4 on zolpidem, continued their treatments. Urological agents were used by 9% of male patients including tamsulosin, alfuzosine and dutasteride. No toxicity was observed. Our cirrhotic patients included 32 (11.3) on Child-Pugh-Turcotte A6 and 19 on Child-Pugh-Turcotte B7-9 (6.7%). RBV in addition of SOF/VEL was administered in no more than 11 of 19 Child-Pugh-Turcotte B patients. These patients were all male, 3 did not complete the assigned treatment course, 3 required RBV dose reductions. All but the three patients who discontinued RBV achieved SVR12. SVR12 was achieved by 353 of 358 (98.6%), (95% CI 96.7%-99.4%) patients in Child-Pugh-Turcotte A and by 16 patients in B (84.2%) (95% CI 62.4%- 94.4%) (p = 0.05). Of 697 patients who were using PPI at the start of treatment, 354 (50.7%) continued their treatment according to SOF/VEL prescribing information. Three hundred and thirty eight (95.5%) of 354 patients who received PPI during treatment achieved SVR12. This rate was not different from the 97.8% rate attained in 622 patients who did not receive PPI (p = 0.48). Characteristics of 20 patients who failed to achieve SVR12 are reported in Table 4. The majority of relapsers were male and naïve. Interestingly, 60% of patients who failed to achieve SVR12 was PWID. This finding highlights the need for closer and more frequent monitoring in PWID. Twelve patients prematurely discontinued treatment, and did not achieve SVR12, 7 of them died. Of the remaining, 4 were noncompliant PWID lost to follow up between week 8–12. One additional PWID with HCC—who died later—discontinued after one dose. Four additional patients only received 8 weeks of treatment but were able to achieve SVR. Two of them were PWID. This large real-world-cohort experience is the first on SOF/VEL enrolling comparable numbers of GT1, GT2 and GT3 patients. SOF/VEL without RBV results in 98.5% SVR12 rates in patients with different stages of fibrosis. SVR12 increases from 98.6% in patients with F0-F2 to 99.7% in F0-F1. By sensitivity analysis, SVR12 in patients with F0-F1 was 100%. Given that, the vast majority of patients currently seeking treatment have mild liver disease and SOF/VEL was used in our study without frequent monitoring, the results attained in F0-F1 patients support test-and-treat strategy with SOF/VEL. Among 282 cirrhotic patients, SVR12 was 97.5%. Our results mirror and improve on the results of registration trials [3,4]. Noticeably, this regimen did not require co-medication changes and cure rates were not affected by concurrent drugs including statins and PPI. Given the difference in potential for drug-to-drug interactions of different pangenotypic regimens our results support the use of SOF/VEL whatever the co-morbidities or co-medications. Source: http://doi.org/10.1371/journal.pone.0215783