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Generic sofosbuvir-based interferon-free direct acting antiviral agents for patients with chronic hepatitis C virus infection: a real-world multicenter observational study

Real-world data regarding the effectiveness and safety of generic sofosbuvir (SOF)-based interferon-free direct acting antiviral agents (DAAs) for patients with chronic hepatitis C virus (HCV) infection remain limited. A total of 517 chronic HCV-infected patients receiving 12 or 24 weeks of SOF-based therapies were retrospectively enrolled in 4 academic centers in Taiwan. The rate of sustained virologic response at week 12 off-therapy (SVR12) and that of treatment completion were assessed. The baseline characteristics and on-treatment HCV viral kinetics to predict SVR12 were analyzed. By evaluable population (EP) analysis, the SVR12 rate was 95.4% (95% confidence interval [CI]: 93.2–96.9%). The SVR12 was achieved in 29 of 34 patients (85.3%, 95% CI: 69.6–93.6%), 130 of 139 patients (93.5%, 95% CI: 88.2–96.6%), 119 of 124 patients (96.0%, 95% CI: 90.9–98.3%) and 215 of 220 patients (97.7%, 95% CI: 94.8–99.0%) who received SOF in combination with ribavirin (RBV), ledipasvir (LDV), daclatasvir (DCV) and velpatasvir (VEL), respectively. Of 517 patients, 514 (99.4%) completed the scheduled treatment. All 15 patients with true virologic failures were relapsers. Two decompensated cirrhotic patients had on-treatment deaths which were not related to DAAs. All 7 patients who were lost to follow-up had undetectable HCV RNA level at the last visit. The SVR12 rates were comparable in terms of baseline patient characteristics and viral decline at week 4 of treatment. In conclusion, generic SOF-based regimens are well tolerated and provide high SVR12 rates in patients with chronic HCV infection.

Effectiveness. Patients received on-treatment serum HCV RNA testing at weeks 4 and 12. For patients receiving 12 and 24 weeks of treatment, serum HCV RNA levels were assessed at treatment weeks 12 and 24 to determine antiviral responses at end-of-treatment (EOT). Furthermore, they received off-therapy serum HCV RNA testing at week 12 to assess SVR 12 . If patients prematurely discontinued treatment, the antiviral response at EOT was assessed at the time of last visit. Patients were considered failure to achieve SVR 12 if they lacked SVR 12 data. We adopted two different endpoints for effectiveness: the evaluable population (EP) which assessed the SVR 12 for patients who received at least one dosage of treatment were included in the analysis, and the per-protocol population (PP) which assessed the SVR 12 by excluding non-SVR 12 patients due to non-virologic failure.
Safety. The rate of treatment completion was assessed for each regimen. The reasons for patients who were lost to follow-up were recorded by the treating physicians. In patients who were seropositive for HBsAg, serum HBV DNA levels were evaluated after the initiation of DAA treatment. HBV reactivation was defined as the presence of HBV DNA level ≥LLOD in patients with baseline HBV DNA level <LLOD, or increase of HBV DNA level >1 log 10 IU/mL in patients with baseline HBV DNA level ≥LLOD 37 . HBV-associated hepatitis was defined as HBV reactivation and hepatitis flare presenting with ALT increase ≥3 times baseline and >100 U/L 38 . Statistical analysis. All analyses were performed using Statistical Program for Social Sciences (SPSS Statistics Version 23.0, IBM Corp., Armonk, New York, USA). The baseline characteristics were shown in median (range) and percentages when appropriate. The viral responses during and after treatment were shown in number and percentages with 95% confidence interval (CI). The stratified analysis of SVR 12 by baseline characteristics and week 4 viral decline were assessed and shown in percentages with 95% CI.

Results
Patient characteristics. Of 593 HCV-infected patients receiving SOF-based IFN-free DAAs, 76 were excluded from the study because of prior DAA exposure, eGFR < 30 mL/min/1.73 m 2 , receiving antiviral regimens not recommended by guidelines, or refusal to provide informed consent. The remaining 517 patients were eligible for the analysis (Fig. 1). Table 1 shows the baseline patient characteristics. Thirty-four (6.6%), 139 (26.9%), 124 (24.0%) and 220 (42.6%) patients receiving SOF in combination with RBV, LDV, DCV and VEL, respectively. Patients receiving SOF/VEL tended to be younger, have a higher percentage of HIV-coinfected patients and a lower percentage of cirrhosis, compared to those receiving other SOF-based regimens. Among patients receiving SOF in combination with NS5A inhibitor, those receiving SOF/LDV tended to have a higher percentage of combining RBV usage, compared to those receiving SOF/DCV or SOF/VEL. All patients receiving SOF/RBV were infected with HCV genotype 2 (HCV-2) and were treated for 12 weeks, whereas all receiving SOF/LDV were infected with HCV-1a, HCV-1b or HCV-6. Sixty-nine (55.6%), one (0.8%), two (1.6%) and two (1.6%) receiving SOF/DCV had HCV-2, HCV-3, HCV-6, and mixed HCV genotype 1b + 2 and 2 + 6 infections. Patients receiving SOF/VEL had HCV-1 to 6 infection. One   had undetectable serum HCV RNA levels at week 4 of treatment and at the end-of-treatment. One Child-Pugh C cirrhotic patient receiving SOF/LDV plus RBV died at treatment day 12 and the HCV RNA level at treatment week 1 was 1,047 IU/mL. The overall SVR 12 Table 2). Among patients who failed to achieved SVR 12 , 15 (2.9%) were relapsers and 9 (1.7%) were lost to follow-up. Among the 15 relapsers, 7 (46.7%) were male, 9 (60%) were treatment-naïve, and 10 (66.7%) had cirrhosis. Eight of the 9 (88.9%) patients who were lost to follow-up had HCV RNA level < LLOD at the last visit (Table 3).
Stratified analysis of baseline characteristics predictive of SVR 12 . Table 4 shows the stratified SVR 12 rates of SOF-based DAA regimens by baseline characteristics and week 4 treatment response. The SVR 12 rates were comparable with regard to age at a cut-off value of 55 years, sex, prior IFN exposure, HBV or HIV coinfection, prior history of HCC, scheduled 12 or 24 weeks of treatment, use of RBV, BMI at a cut-off value of 25 kg/m 2 , ALT quotient at a cut-off of 2, eGFR at a cut-off value of 60 mL/min/1.73 m 2 , baseline HCV viral load at a cut-off value of 6,000,000 IU/mL, HCV genotype, cirrhosis and week 4 viral decline in patients receiving SOF-based regimens. The SVR 12 rates for compensated cirrhotic and decompensated cirrhotic patients were 95.5% (95% CI: 84.9-98.7%) and 80.0% (95% CI: 58. 4 Safety. Five hundred fourteen of 517 (99.4%) patients completed the scheduled treatment. One Child-Pugh C and one Child-Pugh B cirrhotic patients receiving SOF/LDV plus RBV died at treatment day 12 and week 11 due to spontaneous bacterial peritonitis, respectively. One Child-Pugh A cirrhotic patient receiving SOF/VEL declined treatment after week 8 and another 6 patients declined off-therapy follow-ups. The reasons for lost to follow-up in the 7 patients were not related to DAA treatment (Table 3). Among the 41 HCV-infected patients with HBV coinfection, 9 (22.0%) also had HIV coinfection. All the 9 patients received tenofovir (TDF)-based antiretroviral agents (ARTs) and none had baseline detectable serum HBV DNA level or had HBV reactivation after DAA treatment. Nineteen of 32 (59.4%) HBV/HCV-coinfected patients without HIV infection had baseline undetectable serum HBV DNA level; 13 (40.6%) had detectable serum HBV DNA levels (range: 25 to 1,820 IU/ mL). All the 32 patients did not receive oral nucleos(t)ide analogues or peginterferon for HBV prior to DAA treatment. Eighteen (56.3%) patients met the virologic criteria for HBV reactivation after the initiation of DAA treatment. One (3.1%) patient receiving SOF/LDV developed HBV-associated hepatitis at week 8 of treatment. The baseline HBV DNA level was 1,540 IU/mL, which peaked to 54,200 IU/mL at week 8 of treatment. The ALT level was 192 U/L and the serum HCV RNA level was <LLOD at the time of HBV reactivation. No concomitant serum total bilirubin level elevation or signs of hepatic decompensation was present. The patient received entecavir at week 9 and the ALT level normalized after 7 weeks of treatment.    Table 3. Summary of patients who failed to achieve SVR 12 . GT: genotype, Tx: treatment, LTFU: lost-to follow-up, SBP: spontaneous bacterial peritonitis.
In our patients receiving SOF/RBV, all were infected with HCV-2, which reflected the potential suboptimal response rates in patients infected with other genotypes. The SVR 12 rate for SOF/RBV in our study was 85.3%, which was comparable to the response rates in clinical trials 12,13 . Although there were no statistical differences for SVR 12 rates by baseline patient characteristics, our data were in line with VALENCE study that the CIs of the response rates varied widely, probably due to the small case numbers in both studies 13 . In HCV-2 cirrhotic patients receiving SOF/RBV for 12 weeks, the SVR 12 rates in FUSION and VALENCE trials as well as Western real-world practice were 60-82% 12,13,40 . However, the SVR 12 rate in our HCV-2 cirrhotic patients was higher (88.2%) than Western reports and was comparable to the response rates in East-Asian trials [41][42][43] . The factors attributed to the superior response rates in East-Asian patients to Western patients are still unknown. Furthermore, whether extending the treatment to 16 weeks could achieve better response rates in our HCV-2 cirrhotic patients needs further evaluation 12,44 .
The SVR 12 rate of our patients receiving generic SOF/LDV-based therapies was 93.5%, which was comparable to the response rates in patients receiving brand-name agents [14][15][16][17] . Further analysis showed that our patients had similar SVR 12 rates to the phase II and III clinical trials by cirrhosis or genotype/subtype status [14][15][16][17]45 . Furthermore, the SVR 12 rates in our patients receiving SOF/LDV-based therapy were comparable irrespective of baseline patient characteristics, implying the use of generic SOF/LDV can also achieve excellent effectiveness.
About 66.5% of our patients were treated by generic SOF/DCV or SOF/VEL, probably due to the pangenotypic potency and relatively low pill burden compared to SOF/RBV or SOF/LDV 46 . The SVR 12 rates in our patients receiving generic SOF/DCV and SOF/VEL-based therapies were excellent and were comparable to the phase III clinical trials and real-world reports [18][19][20][21]47 . Of 23 decompensated cirrhotic patients receiving generic SOF/DCV or SOF/VEL with RBV for 12 weeks, or SOF/DCV or SOF/VEL without RBV for 24 weeks, all achieved SVR 12 , indicating these agents still had good therapeutic effects in critically ill patients. Furthermore, the response rates remained excellent in patients with unfavorable baseline characteristics. Our data indicated that generic SOF/ DCV or SOF/VEL also had similar effectiveness to brand-name agents.
Regarding our 43 decompensated cirrhotic patients, 39 (90.7%) of them achieved SVR 12 by generic SOF-based DAA therapies. Most patients had improving Child-Pugh class and MELD scores following treatment, implying that the mortality and morbidity can potentially be reduced in these very sick patients.
Among our 32 HBV/HCV coinfected patients not receiving antiviral agents for HBV, the risk of HBV reactivation and the HBV-related hepatitis after generic SOF-based therapies were similar to a recent prospective cohort enrolling 101 HBV/HCV coinfected patients receiving brand-name SOF/LDV, indicating that applying generic DAAs may not increase the risk of HBV reactivation and its associated complication 48 . However, watchful surveillance of HBV activity is still needed to detect and treat HBV-related hepatitis and hepatic decompensation earlier.
Our data showed that the rates of HCV RNA level < LLOD at week 4 of treatment were 88.2-90.3% in patients receiving SOF-based regimens. Although about 10% of our patients remained viremic at week 4 of treatment, the SVR 12 rates were comparable to those who were aviremic at week 4 of treatment. Therefore, the early virokinetics plays a minor role in predicting SVR 12 in patients receiving generic SOF-based therapies 49,50 . Furthermore, our data was also in accordance with a recent meta-analysis that the SVR 12 rates of SOF-based therapies were comparable in Asian patients with or without history of HCC 51 .
In addition to the excellent safety profiles and effectiveness, the prices of generic SOF-based DAA therapies are about 1-2% of the brand-name agents 52 . Based on these advantages, the use of generic SOF-based IFN-free DAA regimens may facilitate the mass treatment and play an important role in the elimination of HCV infection in the world, particularly in resource-constrained countries 53 . However, prudential assessment of severity of hepatic fibrosis, particularly for hepatic decompensation, and HCV genotype are still needed to optimize the treatment strategies.
Although generic SOF-based IFN-free DAAs had excellent safety and effectiveness, several limitations existed in our study. First, we included patients with different characteristics and the direct comparison of effectiveness and safety for each SOF-based regimen was not feasible. Second, the generic DAAs were made by various pharmaceutical companies and the direct comparison of effectiveness and safety was difficult. Third, data regarding the on-treatment constitutional or laboratory adverse events were not available in our retrospective study, making the detailed safety analysis impossible.
In summary, generic SOF-based IFN-free regimens achieved comparably excellent effectiveness and safety to the brand-name agents. These regimens may improve the care of HCV for patients with limited access to the expensive brand-name agents.