China has a large number of patients with HCV infection, but the era of treatment with DAAs officially arrived with the approval of daclatasvir and asunaprevir in 2017. Until now, China’s domestic DAAs were limited and mainly depended on imports, resulting in a considerable economic burden on patients. Among the HCV DAA drugs that have been marketed in China, most only target HCV GT1 and/or GT4 (e.g., sofosbuvir/ribavirin/interferon, danoprevir/ribavirin/interferon, daclatasvir/asunaprevir, ombitasvir/paritaprevir/dasabuvir, elbasvir/grazoprevir). For GT2, GT3, and GT6, which account for about 40% of chronic hepatitis C patients in China, especially for GT3, the choice of DAAs is still limited [11,12,13]. In the phase III trial design of SH229 combined with daclatasvir, the incidence of SVR12 in patients with GT3 compensatory cirrhosis at 24 weeks was only 88% according to the results of the study of sofosbuvir combined with ribavirin in Chinese patients [4]. Clinical trials with similar characteristics to this study mostly compare with historical data when analyzing the SVR12 rate, such as the 85% of the ASTRAL-1 study [14,15,16]. The historical reference value of 88% has been recognized by the National Medical Products Administration.

The efficacy evaluation results of the study showed that the overall SVR12 rate was 98.2% (95% CI 96.5, 99.5), and the efficacy was significantly better than the prespecified historical control of 88% (P < 0.0001).

At post-treatment week 4, five subjects actually had virological relapse, except for one subject who did not complete follow-up; compared with post-treatment week 4, no new virological relapse occurred in the subjects at post-treatment weeks 12 and 24. The results showed that SVR4, SVR12, and SVR24 rates had good consistency. As a whole, the study drug had better efficacy in patients with HCV genotypes 1, 2, 3, and 6, achieving an SVR of more than 95.0%; patients with HCV genotype 2 were more sensitive to the study drug, achieving a 100% SVR. In terms of genotype, the efficacy of the drug was better in patients with HCV genotypes 1a, 1b, 2a, 3b, and 6a, and the SVR12 rate was over 97.0%. In addition, there were only six subjects with genotype 6n enrolled in this study, and one of them failed treatment. Therefore, the low SVR rate among subjects with genotype 6n may be related to the small sample size, which was not statistically significant. The results of multivariate analysis on predictors of virological response rate showed that the presence of cirrhosis was a risk factor for treatment failure, and subjects with cirrhosis were 0.0693 times more likely to achieve SVR12 than those without cirrhosis. The results of drug resistance mutation analysis showed that the efficacy of alfosbuvir plus daclatasvir in Chinese adults with chronic hepatitis C was not affected by baseline NS5A and/or NS5B RASs.

Three pan-genotype hepatitis C drug combinations (sofosbuvir/velpatasvir, glecaprevir/pibrentasvir and coblopasvir hydrochloride/sofosbuvir) have been approved for sale in China, and the study results show that the efficacy in patients with GT-3 hepatitis C is moderate. For example, a phase III study of sofosbuvir/velpatasvir in a predominantly Chinese Asian population showed an overall SVR12 rate of 97% for 12 weeks of sofosbuvir/velpatasvir treatment in patients with gene type 1–6 hepatitis C without cirrhosis or with compensatory cirrhosis. The SVR12 rates of genotype 1, 2, 3a, 3b, and 6 patients were 100%, 100%, 95%, 76%, and 99%, respectively [17]. Two phase III clinical studies in an Asian population dominated by the Chinese population showed that the overall SVR12 rate of glecaprevir/pibrentasvir treatment for 8 weeks was 97.2% (96.9% in the Chinese population) in patients with genotype 1–6 hepatitis C absence of cirrhosis. The rates of SVR12 in genotype 1, 2, 3, and 6 patients were 99.4%, 97.8%, 76.9%, and 100%, respectively (100%, 98.1%, 76.9%, and 100% in Chinese population, respectively) [18]. The China phase III clinical study of the coblopasvir hydrochloride/sofosbuvir therapy regimen showed that the overall SVR12 rate of coblopasvir hydrochloride/sofosbuvir therapy for 12 weeks was 97% in patients with genotype 1–6 hepatitis C without cirrhosis or with compensatory cirrhosis. The rates of SVR12 in genotype 1, 2, 3, and 6 patients were 99%, 96%, 90%, and 98%, respectively [19]. The alfosbuvir /daclatasvir combination has shown a superior virological response rate in patients with GT3 hepatitis C, particularly GT3b hepatitis C.

During the study, the incidence of TEAEs was 82.2% (268/326), and the incidence of ARs was 38.0% (124/326). Lipid metabolism abnormalities such as hypercholesterolemia (10.1%), hyperlipidemia (6.4%), and hypertriglyceridemia (5.8%) were the most common AEs of the alfosbuvir plus daclatasvir hydrochloride treatment regimen. There have been many literature reports highlighting the safety risks of DAAs, which can cause abnormal lipid metabolism abnormalities. Endo et al. found that, in patients with chronic hepatitis C (N = 276) who received sofosbuvir/ledipasvir for 12 weeks or daclatasvir/asunaprevir for 24 weeks and achieved SVR, significant increases in total cholesterol (TC), low-density cholesterol (LDL-C), and high-density cholesterol (HDL-C) levels can be observed [20]; Jain et al. found that, in patients with chronic hepatitis C (N = 50) who received sofosbuvir/daclatasvir for 12 weeks, the levels of TC and LDL-C also showed a significant increase after treatment [21]. Graf et al. reported that patients with chronic hepatitis C (N = 46) who received sofosbuvir/velpatasvir, gorcarrevir/pibrentasvir, elbasvir/grazoprevir, sofosbuvir/velpatasvir/voxilaprevir, and other DAA regimens exhibited a significant increase in the average level of TC, LDL-C, HDL-C, and liver fat content [22]. Doyle et al. reported that patients with chronic hepatitis C (N = 24) who received ombitasvir/dasabuvir/ribavirin also exhibited a significant increase in TC, LDL-C, and triglyceride (TG) levels and liver fat content [23]. The above findings suggest that DAAs exert a significant impact on the lipid metabolism of the host, irrespective of the target and structure of the DAAs. The possible mechanisms by which DAAs affect lipid metabolism are as follows: Upon entering the blood circulation, HCV binds to apolipoproteins (ApoB, ApoE, and ApoC), cholesterol lipids, phospholipids, cholesterol, triglycerides, and other lipids in the blood of the host to form lipoviral particles (LVPs), and subsequently enters liver cells via LDL receptors. This process may cause a decrease in the content of lipids in the blood, while DAAs can reverse the above process. When HCV is cleared, the lipids bound to HCV are released, thus leading to an increase in the concentration of lipids in the blood [22,23,24]. The incidence of SAEs during the study was 7.7% (25/326), none of which were related to the study drug. Most AEs were controllable and tolerable. No patients died during the study.

In the clinical study of alfosbuvir combined with daclatasvir, only historical controls were used for study design, which lacked direct comparison with the effectiveness and safety of listed DAA drugs, and the study results were one-sided. In this study, owing to the widespread spread of COVID-19 in China, it is difficult to collect clinical research data, and part of the interview results are missing. Although these data have been properly processed in the statistical process, it still has a slight impact on the overall trial.

In general, the clinical effectiveness, good tolerability, and safety characteristics of the alfosbuvir plus daclatasvir treatment regimen show a good benefit–risk ratio, supporting the use of this drug in patients with chronic hepatitis C genotypes 1, 2, 3, and 6 who are newly treated or treated with interferon. Treatment with the pan-genotypic regimen of alfosbuvir plus daclatasvir for 12 weeks was highly effective and safe in Chinese patients infected with HCV genotypes 1, 2, 3, or 6, suggesting that this regimen could be a promising option for HCV treatment in China, irrespective of genotype. The clinical benefits of this combination regimen address unmet medical needs in China, which will facilitate the WHO goal of HCV elimination.