Sofosbuvir/Velpatasvir plus Ribavirin for chronic hepatitis C virus genotype 3 infected cirrhotic patients with or without HIV or HBV coinfection: Real-world experience from Southwest China

Abstract

Background: Evidence of direct-acting antiviral (DAA) treatment for refractory chronic hepatitis C (CHC) patients was limited. We aimed to evaluate the effectiveness and safety of Sofosbuvir/Velpatasvir (SOF/VEL) plus Ribavirin (RBV) in cirrhotic patients with hepatitis C virus genotype 3 (GT3) with or without HIV or HBV coinfection.

Methods: From June 2019 to December 2022, CHC GT3 patients who received SOF/VEL plus RBV (dosage of RBV depended on weight) for 12 weeks were enrolled. Liver cirrhosis was diagnosed by clinical presentation . The primary endpoint was sustained virologic response at 12 weeks off-therapy (SVR12). Adverse events (AE)were assessed during treatment.

Results:In total, 285 treatment-naive patients were recruited at the Kunming Third People’s Hospital. Mean age was 48.18±8.27 years-old and 74.04% (211/285) were male. All patients had GT3 HCV infection including 44 patients with GT3a and 241 patients with hepatitis C virus genotype 3b (GT3b) . Among these patients, 39 with HCV/HIV,10 with HBV/HCV, and 1 with HBV/HCV/HIV coinfection. All patients had liver cirrhosis, and 46.67% (133/285) of patients had compensated cirrhosis (CC), while 53.33% (152/285) of patients had decompensated cirrhosis (DCC). 98.95% (282/285) patients achieved SVR12 with SOF/VEL plus RBV treatment for 12 weeks, including 97.72% (43/44) in GT3a and 99.17% (239/241) in GT3b. According to the condition for 285 patients with liver cirrhosis, the SVR12 rate in the CC group was : 99.25% (132/133), the SVR12 rate in the DCC group was: 98.68% (150/152). After 12 weeks of treatment, the APRI score and FIB-4 score in CC group and DCC group were improved, and the improvement in the compensated cirrhosis group was better than that in decompensated cirrhosis group (PAPRI=0.001, PFIB-4=0.001). Mean ALT (from 74±27.23U/L to 39.31±12.22U/L, p<0.05) and AST (from 73.98±25.54U/L to 44.17±15.56U/L, p<0.05) also significantly declined after treatment.1 patient had serious AE of hemolysis but recovered after 2-3 days of interruption of RBV. Most AEs were consistent with clinical sequelae of advanced liver disease or known toxicities of RBV.

Conclusion： SOF/VEL combined with RBV for cirrhotic GT3 hepatitis C patients all obtained high SVR12 (>95%), improved liver function during treatment, and for cirrhotic GT3 hepatitis C patients treatment with SOF/VEL combined with RBV is recommended as early as possible.

Introduction

Hepatitis C is an infectious global epidemic, with an estimated 350,000 deaths per year, mostly due to cirrhosis and hepatocellular carcinoma^[1]. Transmission of HCV, HBV, and HIV had very similar routes, including sexual, mother-to-child, and blood transmission. So co-infection of the three viruses was not rare ^[2]. When HBV/HCV or HCV/HIV co-infection, there existed mutual suppression or interference between the two viruses compared to viral hepatitis infection alone, which accelerates the progression of liver disease and may lead to more serious liver damage， and patients with co-infection had higher risk of cirrhosis, decompensation cirrhosis, and hepatocellular carcinoma (HCC), and faster progress to liver fibrosis, cirrhosis, hepatocellular carcinoma, and end-stage liver disease with poor prognosis ^[3–8]. HCV genotype (GT) 1b is the predominant genotype in China, but GT 3 is predominant in Yunnan province^[9]。 The SVR12 rate of GT 3 hepatitis C is lower than that of other genotypes and was considered refractory to DAA treatment^[10]. One research showed that starting treatment after liver disease progressed to advanced fibrosis or cirrhosis was more difficult to achieve SVR ^[11]. The rate of SVR12 in GT3 hepatitis C patients with cirrhosis was lower than that of patients without cirrhosis, according to another study^[10]. Therefore, GT3 hepatitis C patients with cirrhosis with or without co-infection had become a major global public health problem that needs to be addressed urgently.

Since the widespread use of direct-acting antivirals (DAAs), the treatment course for hepatitis C had been shortened and the cure rate had been increased, making hepatitis C a curable disease ( 95% or higher cure rate)^[12]. In this study, patients with cirrhotic hepatitis C with GT 3 contained HCV, HCV/HIV co-infection, HCV/HBV co-infection, and HCV/HBV/HIV co-infection were selected to observe the efficacy and safety of sofosbuvir-velpatasvir (SOF/VEL) combined with ribavirin (RBV) treatment, which provides a certain reference for the clinical treatment of hepatitis C.

1. Materials And Methods

1.1 Patients

A total of 285 patients with GT 3 HCV infection with liver cirrhosis treated with SOF/VEL plus RBV (dose of RBV depends on body weight) for 12 weeks from June 2018 to December 2021 were included in this study. A total of 44 patients with GT3a, including 28 patients with compensated cirrhotic and 16 patients with decompensated cirrhosis; 241 patients with GT 3b, including 105 patients with compensated cirrhotic and 136 patients with decompensated cirrhosis. In total, there were 235 cases with mono HCV infection, 39 cases with HCV/HIV co-infection, 10 cases with HCV/HBV co-infection, and 1 case with HCV/HBV/HIV co-infection. The Third people’s Hospital of Kunming Ethics Committee approved the study protocol.

1.2 Inclusion criteria

(1) Age 18-60 years (2) HCV-RNA quantitative test >20 IU/mL (3) Genotyping as GT3 (4) Patients with chronic hepatitis C cirrhosis in compensated or decompensated stage (5) Good compliance

1.3 Exclusion criteria

(1) Hepatitis A, D, E viral hepatitis infection; (2) patients with hemoglobin less than 120 g/L; (3) patients with severe mental illness; (4) patients in pregnancy and lactation; (5) patients with combined autoimmune liver disease or hepatomegaly; (6) patients with combined cardiovascular diseases such as severe heart disease, myocardial infarction or acute cerebral infarction.

1.4 Methods

We enrolled 285 patients with GT3 HCV infection who had liver cirrhosis, and 46.67% (133/285) of patients had compensated cirrhosis (CC), while 53.33% (152/285) of patients had decompensated cirrhosis (DCC). Then separated them into GT 3a and GT 3b groups, and stratified them according to their cirrhosis stage. All patients were treated for 12 weeks. HCV-RNA levels , SVR rates and changes in liver function (ALT, AST, TBIL) indexes were measured at baseline, 4 and 12 weeks during treatment, and 12 weeks after the end of treatment, respectively. Among them, sofosbuvir/velpatasvir (manufacturer: Gilead Sciences Ireland UC, import Drug Registration No.: H20180024) at a dose of 400 mg/100 mg once daily, 1 tablet orally with or without food; ribavirin (manufacturer: Zhejiang Zhebei Pharmaceutical Co.; State Drug Registration No. H10940109; lot no.: 2013120123) at a dose of 1,000 mg/d for patients weighing less than 75 kg; 120 mg/d for patients weighing more than or equal to 75 kg. Patients were treated for 12 weeks and followed up for 12 weeks off-treatment.

1.5 Specimen collection and testing

Hepatitis C genotyping was performed by using the Thermo Fisher Scientific 3500XL Genetic Analyzer, and the hepatitis C genotyping kit was purchased from Daan Genetics, Sun Yat-sen University. Hepatitis C virus nucleic acid quantification (HCV-RNA) was detected by real-time fluorescence quantitative PCR, the operating instrument model was CFX96, and the hepatitis C virus nucleic acid quantification kit was purchased from Xi'an Tianlong Company. Biochemical index detection. A fully automatic biochemical analyzer was used for the test, the instrument was Beckman Au5400, and the operating reagents were Wako Glutathione Transaminase Assay Kit and Glutathione Transaminase Assay Kit from Japan. The above operations were strict to the instructions and judgment results, and all were used within the validity period.

1.6 Statistical treatment

SPSS 27.0 statistical software was used for data processing and analysis. The measurement data obeyed normal distribution was described by x¯ ± s, and repeated measures ANOVA was used for comparison between groups; not obeying normal distribution was expressed by M (P25, P75), and the Kruskal- Wallis H test was used for comparison between groups; the count data was described by [n (%)], and the chi-square test was used for comparison between groups. Level α = 0.05, and P < 0.05 was considered a statistically significant difference.

2. Result

2.1 Baseline characteristics 

A total of 285 patients with GT 3 HCV infection with liver cirrhosis were selected (Figure 1). There were no statistical differences in age, gender, and HCV RNA among patients. The RBC, TBIL, ALB, ALP, and CHE indexes of patients in the decompensated stage were higher than those in the compensated stage of cirrhosis, and the differences were statistically significant (P<0.05)(see Table 1，2). 

Tab.1 Baseline clinical characteristics of enrolled patients[x̄±s/n（%）/ M（P25，P75)]

*P<0.05

Abbreviations: GT, genotype; CC, compensated cirrhotic ;DCC, decompensated cirrhosis ;RBC, Red Blood Cell; TBIL, total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; GGT, γ-glutamyl transpeptidase; ALP, alkaline phosphatase; CHE, Cholinesterase; CR, creatinine；UA， Uric Acid. 

Tab.2 Baseline clinical characteristics of enrolled patients[x̄±s/n（%）/ M（P25，P75)]

*P<0.05

Abbreviations: GT, genotype; CC, compensated cirrhotic ;DCC, decompensated cirrhosis ;RBC, Red Blood Cell; TBIL, total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; GGT, γ-glutamyl transpeptidase; ALP, alkaline phosphatase; CHE, Cholinesterase; CR, creatinine；UA， Uric Acid. 

2.2 Virological response after treatment in three groups of patients 

After 4 weeks of antiviral treatment, the total sustained virologic response (SVR 4) rate was 94.38% (269/285),  the total SVR 4 rate in patients with compensated cirrhosis was 93.98% (125/133) (all patients achieved SVR 4 except 3 cases of HCV alone, and 5 patients with HCV/HIV co-infection), and the total SVR 4 rate in patients with cirrhotic decompensation was 94.74/% (144/152 ) (all patients achieved SVR 4 except 3 patients with HCV alone, 4 patients with HCV/HIV co-infection, and 1 patient with HCV/HBV co-infection), with no statistical difference (P=0.783). And the total sustained virological response (SVR 12) rate was 98.94% (282/285) at the end of 12 weeks of antiviral treatment discontinuation, and only one patient with cirrhotic liver cancer in GT3a cirrhosis relapsed after discontinuation, without statistical difference (P=0.642) see Figure 2. in this study No statistical difference was observed in the virological response negative rates [SVR 4 , SVR12] in cirrhotic compensated and cirrhotic decompensated stages (as shown in Table 3).

Tab.3 Comparison of Sustained Virologic Response in Patients with Therapeutic Genotype 3 Hepatitis C [n（%）]  

Abbreviations: RVR , rapid virological response; EVR , early virological response ; SVR, sustained virological response.

3.3 Cirrhosis and liver fibrosis scores in the three groups after treatment 

 In this study, the mean APRI at baseline in the compensated phase of cirrhosis was 5.27, with a total of 115 (86.47%) patients with APRI>2. The mean APRI after 12 weeks of treatment was 1.98, with a total of 27 (20.30%) patients with APRI>2. The difference was statistically significant (P=0.001). The mean APRI value at baseline in the cirrhosis decompensated stage was 5.35 and the total number of patients with APRI>2 was 128 (84.21%), the mean APRI value after 12 weeks of treatment was 2.59, and the total number of patients with APRI>2 was 73 (48.03%), the difference was statistically significant (P=0.001). After 12 weeks of treatment, the mean APRI score decreased by 3.29 (P=0.001) from 5.27 to 1.98 in the group with compensated cirrhosis and by 2.76 (P=0.021) from 5.35 to 2.59 in the group with decompensated cirrhosis. Although no statistical significance was observed numerically in both groups, the proportion of patients with APRI >2 in the cirrhotic compensated stage was lower than in the cirrhotic decompensated stage group at 12 weeks after treatment (P=0.001), as shown in Tables 4, 5 and Figure 3. 

In this study, the mean FIB-4 value at baseline in the compensated stage of cirrhosis was 7.07, and the total number of patients with FIB-4>3.25 was 111(83.46%). The mean APRI value after 12 weeks of treatment was 4.05, with a statistically significant difference from baseline (P=0.001), and the total number of patients with FIB-4>3.25 was 41 (30.83), with a statistically significant difference from baseline (P=0.045). The mean FIB-4 value at baseline in cirrhotic decompensation was 8.39, and the total number of patients with FIB-4>3.25 was 141 (92.76%) . The mean FIB-4 value after 12 weeks of treatment was 6.87, with a statistically significant difference from baseline (P=0.004), and the total number of patients with FIB-4>3.25 was 117 (76.97%), with a statistically significant difference (P=0.001). The proportion of patients with FIB-4>3.25 in the compensated phase of cirrhosis from baseline to 12 weeks post-treatment was lower than that in the decompensated phase of the cirrhosis group (P _baseline=0.014, P _{12 weeks post-treatment}=0.001), and numerically there was also a statistically significant difference between both compensated and decompensated phases of cirrhosis from baseline to post-treatment FIB-4 scores (P _baseline=0.045, P _{12 weeks post-treatment}= 0.003), (as shown in Tables 5 and 6 and Figure 3).

Tab 4. APRI for GT3 CHC patients Before and After Treatment [n（%）]

*P<0.05

Tab 5. FIB-4 for GT3 CHC patients Before and After Treatment [n（%）]

 *P<0.05

Tab 6. APRI and FIB-4 for GT3 CHC patients Before and After Treatment [x̄±s]

*P<0.05

2.4 Biochemical response in the three groups of patients after treatment 

Patients' pre- and post-treatment ALT recurrence rate and AST indexes improved significantly after 4 weeks of treatment (P=0.002), and TBIL indexes improved significantly after 12 weeks of treatment (P=0.002). After stratification by genotype, GT3a and GT3b obtained similar results as overall, with improvement in ALT normality and AST indexes at week 4 of treatment and TBIL indexes at week 12 of treatment. However, after stratification by cirrhosis, patients with cirrhotic decompensation showed significant improvement in AST index after 12 weeks of treatment (P=0.008), compared to the overall improvement after 4 weeks of treatment, patients with cirrhotic decompensation showed improvement in AST index later, and it can be observed in Figure 4 that patients with cirrhotic decompensation showed an increase in AST level after 12 weeks of drug administration but the difference was not statistically significant (P= 0.347), and the time to appearance of improvement in overall AST was consistent in cirrhotic compensated stage, as shown in Table 7. 

Among the patients, the ALT recurrence rate increased from 12.98% at baseline to 80.00%, with statistically significant differences (P<0.05), and all showed a statistically significant difference from the previous observation node with sustained improvement during the observation period. No statistical difference was observed between GT 3a and GT 3b after stratification by genotype. After stratification by cirrhosis stage, there was no statistical difference between the two groups at baseline, but a statistical difference began to appear after the fourth week of treatment in patients with cirrhotic decompensation compared to patients with cirrhotic compensation, and the difference persisted. The ALT recurrence rate was 69.17% in cirrhotic compensated patients at the fourth week of treatment and 48.03% in patients in the decompensated group, with a statistically significant difference (P=0.003). The ALT normalization rate in compensated cirrhosis at week 12 of treatment was 75.94%, and the ALT normalization rate in patients in the decompensated group was 64.47%, with a statistically significant difference (P=0.035). The ALT normalization rate in compensated cirrhosis at the 12th week of discontinuation was 96.24%, and the ALT normalization rate in patients in the decompensated group was 72.37%, with a statistically significant difference (P=0.001), as shown in Table 7 and Figure 4.

Tab 7. Comparison of serum biochemical indexes in patients with hepatitis C virus genotype 3(GT3)[M（P25，P75)]

*P<0.05

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBIL, total bilirubin;

Tab 8 . Changes of ALT normalization rate in patients with hepatitis C virus genotype 3(GT3) before and after treatment[n（%)]

*P<0.05

2.5 safety evaluation

A total of 284 patients (133 with CC and 151 with DCC) completed full treatment, and 1 case was discontinued from RBV due to drug interactions. adverse reactions are shown in Table 8. the incidence of adverse reactions was 43.61% in patients with CC and 71.71% in patients with DCC. The most frequent adverse effects were anemia, elevated bilirubin, and malaise. There were no serious adverse reactions, deaths, or discontinuation of treatment due to adverse events in the study observations, as shown in Table 9.

 Tab 9 . Adverse reaction in patients with hepatitis C virus genotype 3(GT3) [n（%)]

3. Discussion

Because chronic hepatitis C progresses slowly with few or no symptoms, infected patients usually know nothing about it and therefore do not seek prevention, care, or treatment, and most patients are diagnosed with HCV infection only after the onset of symptoms in the late stages of liver disease^[11] .Most patients are diagnosed with HCV infection only after the onset of advanced liver disease. And with the growth of age, studies suggest that the incidence of compensated or decompensated cirrhosis and hepatocellular carcinoma (HCC) will increase significantly over the next 10 to 20 years^[13]. This study evaluated the efficacy and safety of sofosbuvir/velpatasvir in combination with ribavirin in patients with GT3 chronic hepatitis C virus with compensated or decompensated liver stiffness, including 39 patients with HCV/HIV co-infection, 10 patients with HCV/HBV co-infection, and 1 patient with HCV/HBV/HIV co-infection. After 12 weeks of treatment and all patients achieved Among 285 patients, the total SVR rate reached 94.38% (269/285), and a total of 3 patients failed treatment, including 1 patient with GT3a cirrhosis and liver cancer who relapsed after stopping the drug and achieved SVR24 after continuing SOF/VEL treatment; 1 patient with GT 3b combined with HIV in compensated cirrhosis due to drug. One case was a patient with GT 3b combined with HIV in compensated cirrhosis who had not completely cleared the virus after stopping RBV treatment for 12 weeks due to drug interactions and reached SVR24 after extending the drug duration; one case was a patient with GT 3b decompensated cirrhosis who had not reached SVR12 after standardized antiviral treatment and reached SVR24 after following medical advice to change the drug. 

In a phase 3 trial of sofosbuvir/velpatasvir for hepatitis C, the SVR12 rate in patients with compensated cirrhosis after 12 weeks of dosing with SOF/VEL alone for GT 3 patients was 50%^[10]. In contrast, the SVR rates in patients with compensated and decompensated cirrhosis GT 3 after 12 weeks of SOF/VEL combined with RBV in this study reached 99.25% and 96.28%, respectively. Therefore, it can be concluded that SOF/VEL combined with RBV improved the SVR rate in patients with compensated cirrhosis compared to the SOF/VEL regimen alone. Previous studies have confirmed that the SVR rate is related to the risk of liver cancer, and increasing the SVR rate of patients can effectively reduce the risk of liver cancer^[14,15]. The risk of hepatocellular carcinoma can be effectively reduced by increasing the SVR rate. Therefore, SOF/VEL combined with RBV is recommended for patients with cirrhotic GT3 hepatitis C. 

APRI score is an AST and platelet ratio index, which can be used for the assessment of cirrhosis, with an APRI > 2 in adults indicating that the patient had developed cirrhosis^[9]. The FIB-4 score is a ratio index based on ALT, AST, platelet count, and patient age, and can be used for fibrosis with significant fibrosis (equivalent to Metavir score ≥ F2)^[9]. In this study, APRI score and FIB-4 in both compensated and decompensated stages of cirrhosis were effectively improved after treatment, with better improvement in the compensated than in the decompensated stage, which may predict an improvement in cirrhosis after treatment, but better improvement in compensated cirrhosis.

 The overall ALT recurrence rate, AST index, and TBIL index values of the patients in this study improved after treatment, but after stratification according to the compensated or decompensated stage of cirrhosis, patients in the decompensated stage of cirrhosis showed a later improvement in AST than in the compensated stage, and the ALT recurrence rate was consistently lower than that in the compensated stage of cirrhosis from the fourth week after treatment. The results of this study showed that although antiviral therapy could improve liver function in patients with cirrhotic decompensation, the improvement of liver function in patients with the cirrhotic compensated stage was significantly better than that in cirrhotic decompensation. This suggests that we should increase the publicity of hepatitis C, improve the diagnosis rate and treatment rate of hepatitis C, and try to avoid the occurrence of cirrhotic decompensation. 

After patients took RBV treatment, the incidence of adverse effects was 43.61% in patients with compensated cirrhosis and 71.71% in patients with decompensated stage. The incidence of adverse reactions was higher in decompensated stage than in compensated stage. The overall hemoglobin decreased, with severe anemia in the decompensated phase accounting for 7.24% and the incidence of severe anemia in the compensated phase was 0.75%. The hemoglobin increased after reducing the drug dosage and returned to the pre-treatment level after stopping the drug. There was only one case of discontinuation due to drug interactions while taking RBV. Although there were no serious adverse reactions in this study, a certain percentage of patients with cirrhosis, especially in the decompensated stage of cirrhosis, still had severe anemia, so it is recommended to regularly test the hemoglobin and bilirubin of patients with cirrhosis during the use of RBV to prevent the occurrence of serious adverse reactions. 

Our study still had some limitations due to the observation of 72.37% ALT recurrence in cirrhotic decompensated GT3 hepatitis C patients only 12 weeks after drug discontinuation, but how it will subsequently progress and be treated remains unclear, as well as the long-term clinical benefit of achieving SVR12 in cirrhotic patients remains unclear and needs further study. 

In conclusion, SOF/VEL combined with RBV for cirrhotic GT3 hepatitis C patients all obtained high SVR12 (>95%), improved liver function during treatment, and early treatment with SOF/VEL combined with RBV regimen is recommended for cirrhotic GT3 hepatitis C patients.

Declarations

Acknowledgements

We gratefully thank the Kunming Third People’s Hospital for providing the data platform.

Author contributions 

Yongrui yang , Ti wu and Nihong Lu contributed equally.TW drafted the manuscript with guidance from YRY and NHL. KH and ZRZ made substantial contributions to the conception of the work. HWL were responsible for acquisition and interpretation the date and figures. All authors read and approved the final manuscript. 

funding.

This study had no funding.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the author on reasonable request.

This study was approved by the Ethics Committee of the Kunming Third People’s Hospital（No. 2019091825 )，which waived the need for informed consent.

Consent for publication

Not applicable.

Competing interests

The authors have no conflicts of interest to disclose.

References

1. Guidelines for the Care and Treatment of Persons Diagnosed with Chronic Hepatitis C Virus Infection [Internet][EB/OL]//PubMed. (2018-07)[2022-10-12].
2. SCHLABE S, ROCKSTROH J K. Advances in the treatment of HIV/HCV coinfection in adults[J/OL]. Expert Opinion on Pharmacotherapy, 2018, 19(1): 49-64.
3. Ning Zhang , Chengjun xu , Yanwei yu, al . Current status and research progress of HBV/HCV superinfection [J]. International Journal of Gastroenterology, in China ,2015, 35(3): 190-193.
4. THOMSON E C, FLEMING V M, MAIN J, al. Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men[J/OL]. Gut, 2011, 60(6): 837-845.
5. BENHAMOU Y. Hepatitis B in the HIV-Coinfected Patient[J]. J Acquir Immune Defic Syndr, 2007, 45: 9.
6. LANDRUM M L, FIEBERG A M, CHUN H M, al. The Effect of Human Immunodeficiency Virus on Hepatitis B Virus Serologic Status in Co-Infected Adults[J/OL]. PLoS ONE, 2010, 5(1): e8687.
7. THEIN H H, YI Q, DORE G J, al. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis[J/OL]. AIDS, 2008, 22(15): 1979-1991.
8. GRAHAM C S, BADEN L R, YU E, al. Influence of Human Immunodeficiency Virus Infection on the Course of Hepatitis C Virus Infection: A Meta‐Analysis[J/OL]. Clinical Infectious Diseases, 2001, 33(4): 562-569.
9. Chinese Society of Hepatology and Chinese Society of Infectious Diseases;Chinese Medical Association; Guidelines for hepatitis C prevention and treatment (2019) [J/OL]. Chinese Journal of Viral Diseases, 2020, 10(1): 26-46.
10. WEI L, LIM S G, XIE Q, al. Sofosbuvir–velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial[J/OL]. The Lancet Gastroenterology & Hepatology, 2019, 4(2): 127-134.
11. MORGAN R L, BAACK B, SMITH B D, al. Eradication of Hepatitis C Virus Infection and the Development of Hepatocellular Carcinoma: A Meta-analysis of Observational Studies[J/OL]. Annals of Internal Medicine, 2013, 158(5_Part_1): 329.
12. PAWLOTSKY J M, NEGRO F, AGHEMO A, al. EASL recommendations on treatment of hepatitis C: Final update of the series☆[J/OL]. Journal of Hepatology, 2020, 73(5): 1170-1218.
13. MCGARRY L J, PAWAR V S, PANCHMATIA H R, al. Economic model of a birth cohort screening program for hepatitis C virus[J/OL]. Hepatology, 2012, 55(5): 1344-1355.
14. CARDOSO A C, MOUCARI R, FIGUEIREDO-MENDES C, al. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: Incidence and survival in hepatitis C patients with advanced fibrosis[J/OL]. Journal of Hepatology, 2010, 52(5): 652-657.
15. VELOSA J, SEREJO F, MARINHO R, al. Eradication of Hepatitis C Virus Reduces the Risk of Hepatocellular Carcinoma in Patients with Compensated Cirrhosis[J/OL]. Digestive Diseases and Sciences, 2011, 56(6): 1853-1861.