FormalPara Key Summary Points

Why carry out this study?

 Data on hepatitis C virus (HCV) treatment in certain populations in Taiwan are limited.

 Data on HCV treatment with sofosbuvir/velpatasvir (SOF/VEL) from large-scale real-world settings in Taiwan are limited.

 Efficacy and safety of SOF/VEL was analyzed in 3480 patients using a nationwide HCV database.

What was learned from this study?

 Overall, 99.4% of patients with HCV treated with SOF/VEL, with and without ribavirin, achieved cure, regardless of baseline characteristics and patient population.

 Treatment with SOF/VEL was well tolerated in those with severe liver disease and comorbidities.

 Treatment with SOF/VEL did not worsen kidney function in patients with HCV and chronic kidney disease.

Introduction

Hepatitis C virus (HCV) is a global public health concern, with over 71 million people infected around the world. Chronic HCV is recognized as a common cause of cirrhosis, hepatocellular carcinoma (HCC), liver transplantation, and liver-related deaths [1]. Since the introduction of direct-acting antivirals (DAAs), the expectation is that 95% of treated patients will be cured of HCV—defined as a sustained virologic response 12 weeks after the end of therapy (SVR12) [2]. Achieving SVR12 is associated with a decreased risk of liver disease progression and its complications, including liver decompensation, portal hypertension, and death [3, 4].

Sofosbuvir/velpatasvir (SOF/VEL), a protease inhibitor (PI)-free 12-week regimen for patients with chronic HCV, has demonstrated SVR12 rates of 95–100% in over 1100 clinical trial patients with HCV genotypes 1–6 [5,6,7]. Efficacy in clinical trials has translated into effectiveness in clinical practice, evidenced through multiple real-world studies [8,9,10]. Clinical trials in an Asian population have shown similar results to those in western parts of the world [25].

HCV populations have more comorbidities that may aggravate the progression of fibrosis, such as obesity and insulin resistance and coinfection with HIV or HBV. The development of hepatic and extrahepatic diseases, such as circulatory disease and renal disease, can lead to increased mortality in patients with chronic HCV [26]. In Taiwan, the most common comorbidities are diseases of the digestive system (40.1%), circulatory system (38.7%), and endocrine/nutritional/metabolic diseases (35.2%). These diverse comorbidities in the Taiwanese population are reflected in this current cohort and it is encouraging that high SVR12 rates were achieved with SOF/VEL in persons who inject drugs (99.5%), patients with active HCC (98.5%), and those coinfected with HBV (98.8%) or HIV (96.9%). This suggests that SOF/VEL was well tolerated in patients with comorbidities and these rates of cure match or exceed those of previous clinical and real-world studies [27,28,29].

Currently, there is a large gap in data on the effectiveness and safety of SOF/VEL in patients with decompensated cirrhosis in Taiwan. As the use of PI-based regimens is contraindicated in patients with decompensated cirrhosis, such data are essential for guiding patients and physicians in treatment decision-making and advising healthcare policies on treatment coverage. To the best of our knowledge, this is the largest cohort study on the efficacy and safety of SOF/VEL treatment in patients with decompensated cirrhosis in Taiwan. The high SVR12 rates achieved in this patient group in this study (100% of 114 patients) demonstrate the high effectiveness and value of a PI-free regimen, such as SOF/VEL, in this patient group.

In patients who did not achieve SVR12, HCV RNA viral load over 6,000,000 IU/mL and HCV genotype 3 infection were the factors found to be significantly associated with the risk of not achieving SVR12. However, as only three patients with genotype 3 did not achieve SVR in the TACR cohort, and all patients with genotype 3 and high viral load achieved cure, this statistically significant difference is unlikely to have a clinical impact, especially given that the majority of the chronic HCV population in Taiwan is infected with genotype 1 or 2 (as also reflected in this cohort). Despite having a very low cutoff value for drug adherence (the SIMPLIFY study quantified low adherence as below 90% [30]), the majority of patients (5/9) with adherence below this 60% threshold achieved SVR12 with SOF/VEL. However, adherence is important to ensure treatment effectiveness.

As the metabolite of SOF is renally cleared, SOF-based regimens were previously not recommended in patients with severely impaired renal function (CKD stage 4 or 5, eGFR < 30 mL/min/1.73 m2). However, despite elevated plasma levels of sofosbuvir and its metabolite GS-331007 in patients with renal impairment, increasing evidence supports the safety and effectiveness of SOF-based regimens in this patient population [31, 32], including those with liver cirrhosis [32] and uremic patients on dialysis [33]. In November 2019, the US Food and Drug Administration (FDA) amended the package inserts for SOF-based regimens to allow use in patients with renal disease, including those with an eGFR < 30 mL/min/1.73 m2 and those on dialysis, and the Taiwan consensus statement on the management of hepatitis C recommends SOF/VEL as one of the treatment options for patients with stage 4 or 5 CKD [17]. This is supported by data from this cohort that demonstrated a lack of fluctuation in eGFR levels across some CKD stages and, notably, all patients with CKD stage 4 achieved SVR12. In patients with eGFR < 90 mL/min/1.73 m2 and cirrhosis, eGFR increased significantly, showing that not only could renal function deterioration be halted but it could also be improved in some patient groups typically seen as “difficult to cure”.

The majority of patients tolerated treatment well with only 10% of patients experiencing adverse events and 0.6% experiencing serious adverse events, the majority of which were experienced in the ribavirin-added group. Only three patients discontinued treatment as a result of adverse events and these were not considered to be related to SOF/VEL therapy. It should be noted that the adverse events observed could be due to ribavirin or the severity of disease. Although, with the high SVR12 rates achieved irrespective of ribavirin, it raises the question whether a simplified therapy without ribavirin would be more beneficial. This has been highlighted by a recent phase 3 trial from Japan that demonstrated SOF/VEL without ribavirin was highly effective and well tolerated in patients with decompensated cirrhosis. The study found the addition of ribavirin did not improve efficacy, but increased toxicity [34].

There were limitations identified in this cohort study. First, this was a retrospective-prospective study, where patients treated with SOF/VEL before February 2021 were eligible for inclusion. However, the data analyzed were obtained prospectively in accordance with the regulations of Taiwan’s Health Insurance Administration for DAA therapy. Second, as a result of limited numbers of certain types of patients, such as patients with HCV genotypes 4 and 5, the treatment outcomes for those patients may be lacking. Despite these limitations, the TACR includes data from patients treated at a range of settings across Taiwan, including medical centers, regional hospitals, and local clinics. Furthermore, as no specific exclusion criteria were applied to the study population, this is a true reflection of the real-world management of patients with chronic hepatitis C in this country.

Conclusion

A simple, pangenotypic, protease inhibitor-free treatment that results in high SVR12 rates with and without ribavirin, regardless of genotype, cirrhosis, severity of liver disease, and comorbidities is of value in Taiwan and across Asia. The confirmation of the high SVR12 rates with SOF/VEL with and without ribavirin supports use of this regimen in a more diverse population, including those with decompensated cirrhosis and CKD.