Treatment Outcomes of Sofosbuvir/Velpatasvir/Voxilaprevir in Direct-Acting Antiviral-Experienced Hepatitis C Virus Patients: A Systematic Review and Meta-Analysis

About 5% of chronic hepatitis C (CHC) patients experienced treatment failure with direct-acting antiviral (DAA) treatment. The global data on the practice and treatment outcomes of Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) in DAA-experienced CHC patients remains sparse. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of SOF/VEL/VOX as a salvage treatment in DAA-experienced CHC patients. We searched five electronic databases from inception to 31 January 2023. The study outcomes were SVR12 and treatment-related adverse effects, with subgroup analysis performed based on genotype, cirrhosis, HCC, prior SOF/VEL exposure, and region. We identified and analyzed data from 24 studies (2877 DAA-experienced CHC patients); 17.2% had prior SOF/VEL exposure, 25% received ribavirin with SOF/VEL/VOX, and 42% had pre-treatment resistance-associated substitution (RAS) testing performed. Eastern Mediterranean had a higher pooled SVR12 than the America and Europe regions (p < 0.05). Predictors of SOF/VEL/VOX failure were genotype 3, active HCC, baseline cirrhosis, and prior SOF/VEL. Baseline RAS mutation and ribavirin supplementation were not associated with higher SVR12. Treatment discontinuation because of drug-related adverse events was uncommon (10 studies, 0.2%). In summary, SOF/VEL/VOX is efficacious and safe for retreatment in DAA-experienced CHC patients, even with RAS mutation. Our findings support SOF/VEL/VOX as a first-line rescue treatment for DAA-experienced CHC patients.


Introduction
Chronic hepatitis C (CHC) infection affects 56.8 million people globally, with about 1.5 million new infections every year, resulting in 400,000 deaths each year [1]. The World Health organization (WHO) has set a goal to reduce new HCV infections by 90% and death by 65% by 2030 [1]. While the global incidence of CHC has reduced from 71 million to 56.8 million, only 11 countries are currently on track to meet the WHO's 2030 elimination target [2]. Virological cure significantly reduces liver-related complications and improves survival in CHC patients [3]. Sofosbuvir-based DAA has shown to achieved high SVR12 in real-world settings, even among HCV patients with genotype 3 [4,5]. Despite that the introduction of highly effective direct-acting antiviral drugs (DAAs) has revolutionized the CHC treatment, up to 5% of CHC patients still failed to achieve a sustained virological response at week 12 (SVR12) using DAA [6].
Treatment options remain limited in DAA-experienced CHC patients who fail to achieve SVR12. Retreatment of CHC patients with DAA failure could be challenging because of the emergence of resistance-associated substitution (RAS). Current guidelines recommend Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) as a salvage treatment for DAA-experienced CHC patients who failed to achieve SVR12 [7]. SOF/VEL/VOX is a once-daily, oral-administering CHC treatment consisting of NS3, NS5A, and NS5B-inhibitor (Sofosbuvir 400 mg, Velpatasvir 100 mg, and Voxilaprevir 100 mg) with pangenotypic potency. The POLARIS I and 4 phase III trial reported a high treatment response among DAA-experienced CHC patients receiving SOF/VEL/VOX, with SVR12 ranging between 95% and 100% [8].
The global data on practice and treatment outcomes of SOF/VEL/VOX remained lacking, especially in regions such as Asia and Africa. Although some studies reported a lower SVR12 among CHC patients with liver cirrhosis or genotype 3, which is prevalent in south Asia [9,10], such findings were not consistently reported [11]. Furthermore, the predictors of treatment failure and the role of ribavirin in CHC patients receiving SOF/VEL/VOX remains unclear. Real-world data are important to determine the efficacy and safety of SOF/VEL/VOX among DAA-experienced CHC patients who were ineligible for clinical trials. To address these gaps, we performed a systematic review and meta-analysis to determine the efficacy and safety of SOF/VEL/VOX as a salvage treatment among DAA-experienced CHC patients. We also aim to determine the predictors of treatment failures following SOF/VEL/VOX among DAA-experienced CHC patients.

Eligibility and Search Strategy
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline for data extraction and reporting [12]. With the help of a medical librarian, we identified all potential literature through a comprehensive search of five electronic databases (PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and Web of Science) from inception up to 31 January 2023. The search keywords included a combination of "hepatitis C", "Sofosbuvir", "Velpatasvir", "Voxilaprevir", and "virological response" (Supplementary Table S1). We also searched the references of all included studies for potential eligible studies.

Study Selection
We included all studies that met one of the following inclusion criteria, regardless of publication dates and publication status. Our inclusion criteria were as follows: (1) DAA-experienced, adult CHC patients (age > 18 years old) treated with 12 weeks of SOF/VEL/VOX, with or without Ribavirin, and (2) reported data on either SVR12 or adverse events. Our exclusion criteria were (1) paediatric CHC patients; (2) animal studies; (3) studies that did not report study outcomes; (4) case reports or case series with less than 10 patients; (5) reviews, editorials, or guidelines; and (6) clinical trials. Three authors (P.D., K.L.A.T., and J.E.N.) independently performed the initial screening of the title and abstract identified in the primary search for eligibility. Any discrepancy in the article selection was resolved by discussion and consensus with the senior author (W.Y.J.).

Data Extraction and Quality Assessment
The data from each study were independently extracted using a standardized form. We contacted the corresponding author to verify any missing information. The data extracted included demographics of the study participants (age and genotype of hepatitis C virus), location, sample size, RAS testing at baseline, SVR12, concurrent use of ribavirin (RBV), and treatment-related adverse events requiring discontinuation of treatment.

Outcomes Assessed
The outcomes studied were as follows: (1) SVR12 (both the intention-to-treat (ITT) and per-protocol (PP) analysis) and (2) frequency of adverse events leading to treatment discontinuation. The ITT analysis included all subjects treated with SOV/VEL/VOX, while the PP analysis only included SOF/VEL/VOX-treated CHC patients with available SVR12 results. Subgroup analysis was performed based on region, HCV genotype, baseline cirrhosis status, prior SOF/VEL exposure, hepatocellular carcinoma, RAS mutation, and concurrent use of ribavirin.

Data Synthesis and Analysis
We used Review Manager Software version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) to perform our meta-analysis. The effect measures were estimated using the odds ratio (OR) for categorical outcomes and mean difference (MD) for continuous outcomes together with the respective 95% confidence interval (95%CI). The meta-analysis was performed using the random-effects model. A p-value of less than 0.05 was considered to be statistically significant. Study heterogeneity was assessed by the I 2 % statistics.

Quality Assessment
The quality of all included studies was independently assessed by three authors using the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I) tool (non-randomized studies) [13] and the Cochrane risk-of-bias tool for randomised trials (RoB 2) (randomised studies) [14] as low risk of bias, some concerns of bias, or high risk of bias.

Population Characteristics
A total of 2887 DAA-experienced CHC patients from 24 studies were patients received 12 weeks of SOF/VEL/VOX, with or without ribavirin. The acteristics of the included studies are summarised in Table 1

Adverse Events
From a total of 1283 DAA-experienced CHC patients received SOF/VEL/VOX pooled risk of severe adverse events that occurred during SOF/VEL/VOX treatmen 1.94% (95%CI: 1.2-2.8%). The types of serious adverse events are summarised in Su mentary Table S3. Treatment-related adverse events in patients with decompen

Adverse Events
From a total of 1283 DAA-experienced CHC patients received SOF/VEL/VOX, the pooled risk of severe adverse events that occurred during SOF/VEL/VOX treatment was 1.94% (95%CI: 1.2-2.8%). The types of serious adverse events are summarised in Supplementary Table S3. Treatment-related adverse events in patients with decompensated cirrhosis were only reported in one study, where three patients developed treatment-related SAE, namely abdominal pain (n = 2) and acute kidney injury (n = 1).

Discussion
In this meta-analysis, we found that SOF/VEL/VOX is an efficacious and safe salvage therapy among DAA-experienced CHC patients. The pooled SVR12 was high and treatment discontinuation due to treatment-related SAE was uncommon. Predictors for a lower SVR12 rate by SOF/VEL/VOX were genotype 3, active HCC, baseline cirrhosis, decompensated cirrhosis, and prior SOF/VEL exposure. Meanwhile, the presence of baseline RAS mutation and addition of ribavirin to SOF/VEL/VOX was not associated with higher SVR12. The higher overall SVR12 among the Eastern Mediterranean studies is likely attributed to a lower proportion of patients with GT3 infection and liver cirrhosis.
SOF/VEL/VOX, being a protease-inhibitor based DAA, was discouraged in patients with decompensated cirrhosis because of potential toxicity from delayed drug clearance. Among 34 decompensated CHC patients treated with SOF/VEL/VOX in five different studies [9,[30][31][32][33], none experienced treatment-related adverse events requiring early treatment cessation. SAE among decompensated cirrhosis patients was reported only in one study [29]. Meanwhile, hepatic decompensation had also been reported among compensated cirrhosis patients receiving SOF/VEL/VOX. In a large multinational registry of advanced CHC cirrhosis patients (up to CTP-class B or MELD score or 15) receiving DAA, the risk of liver decompensation was not significantly different between protease inhibitor-based versus non-protease inhibitor-based DAA [35]. Until further data are available among decompensated cirrhosis patients with CTP-class C or MELD score beyond 15, liver transplant should be considered as a definitive treatment in these patients, with protease-inhibitor-based DAA reserved for transplant-ineligible patients with close monitoring.
Current EASL guidelines recommend the use of RBV with SOF/VEL/VOX in patients with a higher risk of treatment failure; however, the benefits of routine addition of RBV remain unclear [36]. We found that RBV did not significantly improve SVR12 in DAAexperienced patients. Given the potential side effects, such as causing anemia and jaundice, it should not be used routinely as there were no substantial benefits noted in this metaanalysis. Future studies are needed to evaluate the benefit of RBV among "difficult-to-treat" CHC patients during retreatment with SOF/VEL/VOX. This meta-analysis provides a comprehensive global perspective on the effectiveness and safety of SOF/VEL/VOX among DAA-experienced CHC patients. Prior to this, information on practice and treatment outcomes of SOF/VEL/VOX use among Asian and African population was limited. We acknowledge that there are limitations when interpreting our findings. Most studies did not report the compliance and potential drug interaction among patients receiving SOF/VEL/VOX. The number of patients within subgroups of decompensated cirrhosis was small because the current guidelines discourage the use of SOF/VEL/VOX in these patients. Nevertheless, the results of this meta-analysis provide important data to support the recommendation of using SOF/VEL/VOX as a first-line option among DAA-experienced CHC patients and could be considered level 1 evidence.
To conclude, SOF/VEL/VOX is a well-tolerated and highly effective rescue therapy among DAA-experienced CHC patients who failed to achieve SVR12. Predictors of treatment failure include GT3, liver cirrhosis, and active HCC. Safety data of SOF/VEL/VOX among decompensated cirrhosis patients should be investigated in further studies.  Data Availability Statement: Data will be made available upon reasonable request.