Antiviral therapy for chronic hepatitis C has been going on for more than 10 years, during which clinical trials and clinical practice have established the clinical status of interferon combined with ribavirin in the treatment of chronic hepatitis C and the criteria for evaluating therapeutic efficacy. Since the acquisition of sustained viral response (defined as blood HCV RNA remaining negative 24 weeks after discontinuation of drug therapy) after treatment predicts maintenance of negativity during long-term follow-up and is associated with a reduction in the incidence of mortality and complications associated with liver disease in patients, a reduction in the incidence of liver transplantation and liver cancer, and even a reduction in the risk rate of death from all causes in patients with chronic hepatitis C, sustained viral response The goal and efficacy of antiviral therapy for hepatitis C has become an indicator for evaluation. Current exploration of treatment options and research on new drugs are being conducted to find ways to improve SVR. Among the many factors influencing efficacy, genotype and viral load among viral factors, degree of liver fibrosis and IL-28B genotype among host factors, type of interferon and ribavirin (RBV) dose among drug factors, and more importantly, viral response during treatment and its prediction of efficacy, determination of course of treatment and direct-acting antiviral agents (DAAs) are the most important factors. The clinical application of direct-acting antiviral agents (DAAs) has made great progress. They have also laid a solid foundation for the personalization of antiviral therapy for chronic hepatitis C.
Polyethylene glycol interferon in combination with ribavirin remains the cornerstone of current treatment for chronic hepatitis C.
Although the antiviral treatment of chronic hepatitis C has gone through a history of more than 10 years of development, the two milestones of progress from common interferon to pegylated interferon (PEG-IFN) and from interferon monotherapy to combined ribavirin have led to continuous improvement in antiviral efficacy. To date, a standard treatment regimen has been established, namely pegylated interferon alpha in combination with ribavirin. Among the drugs studied, boceprevir and telaprevir were approved for marketing by the U.S. National Food and Drug Administration and the European Medicines Agency in 2011. Although both drugs can improve SVR acquisition rates, the use of single drugs, due to viral mutation and resistance within 14 days, DAAs in clinical studies since then have required combination with PEG-IFN/RBV as the base therapy (for triple therapy). It is also difficult to obtain clinical application of direct antiviral action drugs in China in recent years, and pegylated interferon in combination with ribavirin will remain the cornerstone of chronic hepatitis C treatment for a long time to come.
Influence of viral genotype and host IL-28B genotype on efficacy.
Many factors can influence the efficacy of antiviral therapy for HCV, with the host IL-28B (rs12979860 ) genotype, viral genotype, and interferon type being the most important. Viral genotype determines the course of treatment and the need for combination therapy with small molecule compounds. The 2011 US liver disease practice guidelines propose triple therapy with PEG-IFNα/RBV and boceprevir or telaprevir as the standard of care for patients with genotype 1. In studies of the effect of viral genotype on efficacy, viral genotype was a determinant of duration of therapy, with 48 weeks for genotype 1/4 and 24 weeks for genotype 2/3. Even so, there were differences in response to interferon between genotypes, with genotype 2 being more susceptible to interferon than genotype 3. The results of a meta-analysis study also showed significant differences in SVR between genotype 2 and genotype 3 (74% and 68%, respectively). One study showed that genotype 3 has a faster progression of liver disease, which may be related to the higher incidence of fatty liver and insulin resistance in genotype 3. Patients with genotype 3 without RVR had an SVR rate of only 52% at 24 weeks of treatment, and even extending the course of treatment to 36 weeks did not improve the SVR rate. This suggests that the treatment course needs to be extended to 48 weeks or even longer for genotype 3 patients without RVR.
Among the studies on factors affecting HCV antiviral therapy, an important finding in recent years is the effect of IL-28B genotype on efficacy. il-28B is IFN-λ3, which is required for Toll-like receptor (TLR)-mediated antiviral protection. iFN-λ induces a stable increase in interferon-stimulated gene (IFN- stimulated gene (ISG) expression, whereas type I interferon induced expression is rapid and transient, thus IFN-λ may induce a slow and sustained antiviral response. In the study of the effect of IL-28B genotype on regression after HCV infection, the IL-28B gene type CC was associated with spontaneous clearance of acute HCV infection, and in all studies of antiviral therapy for chronic hepatitis C, the SVR of the IL-28B gene type CC was higher than that of the CT and TT types,In the IDEAL study, analysis of factors affecting SVR acquisition showed that IL-28B In the IDEAL study, analysis of factors affecting SVR acquisition showed that IL-28B had the highest predictive power for SVR acquisition in PEG-IFN/RBV treatment with an OR of 5.2 (95% CI, 4.1-6.7), while IL-28B had an OR of 24.3 (95% CI, 2.27-259.9) for SVR acquisition in Chinese patients. “The results of the 11th Five-Year Plan study showed that the prevalence distribution of IL-28B CC type in the Chinese population was more than 80%, which may explain the higher antiviral efficacy in Asian patients with chronic hepatitis C than in European and American countries. Although the use of DAA significantly increased SVR rates, one study showed no difference in SVR rates between standard PEG-IFN/RBV treatment and PEG-IFN/RBV + DAA treatment in patients with IL-28B CC type who obtained RVR. Therefore, it is important to test IL-28B genotype before antiviral therapy in patients, especially in refractory patients with genotype 1, severe liver fibrosis and high body weight.
Treatment guided by viral response in therapy is essential to ensure SVR acquisition.
SVR acquisition is the goal of chronic hepatitis C treatment, and to achieve this goal, there should first be negative HCV RNA (to below the detection line) during treatment, and on the basis of achieving and maintaining HCV RNA below the detection line during treatment, and then pursuing sustained viral negativity at the end of treatment. Although there are many factors that influence efficacy, viral response during and after treatment cessation is a combination of the effects of various factors. Based on baseline HCV RNA testing prior to treatment, it is important to monitor HCV RNA during treatment and guide further treatment (response guide treatment, RGT) based on the response of the virus during treatment. The prediction of SVR by on-treatment viral response allows early identification of patients who cannot obtain SVR to avoid unnecessary treatment; timely adjustment of treatment regimen for those with poor response to obtain SVR; and allows patients with good response to avoid unnecessary prolongation of treatment based on maximizing the rate of obtaining SVR.
In order to more accurately predict the achievement of SVR, the viral response at different time points in therapy and its ability to predict the achievement of SVR, and the requirement for a course of therapy that maximizes the achievement of SVR, the 2011 EASL guidelines provide a clearer and more precise definition of viral response in therapy than ever before.
We are given clear requirements: 1) treatment should be discontinued for non-responders and partial responders due to difficulty in obtaining SVR; 2) sensitive detection reagents must be used; 3) an effective response must bring HCV RNA below the detection line and be maintained until the end of treatment; and 4) the length of time that negative HCV RNA persists determines the probability of SVR acquisition.
In the current situation in China, since most medical units have difficulty in achieving a sensitivity of <50 IU/ml, it is important not to assume that a negative response indicates the acquisition of RVR, EVR and DVR, and this will often lead to a relapse after discontinuation of treatment. The results of the "11th Five-Year Plan" major project showed that 37.33% and 20.83% of patients with non-RVR and non-EVR detected by Roche COBAS TaqMan HCV Test were detected with RVR and EVR by domestic reagents, respectively. discontinuation at 48 weeks of treatment according to guidelines will result in relapse in a large number of patients, and one study noted that to maximize the probability of obtaining SVR, it is necessary to achieve <50 IU/ml of virus and maintain treatment for 44 weeks. In the determination of the prediction of SVR by viral response, although the acquisition of EVR is the ruler in the decision to discontinue the drug, the acquisition or not of RVR has an equally major significance. One study showed that the negative predictive value of SVR acquisition was 93% in patients with HCV RNA decreases of less than 1 log at 4 weeks of treatment. This suggests that the regimen should be adjusted promptly in such patients. Although IL-28 B genotype had the strongest predictive power of all baseline predictors of SVR, the predictive value of IL-28B decreased or disappeared when RVR was also included in the analysis of predictors.
Effect of interferon type, ribavirin dose on efficacy and principles of adjustment.
The difference in molecular weight between regular interferon and pegylated interferon leads to differences in drug metabolism and kinetics consisting of absorption, volume of distribution, drug degradation and excretion of different drugs after injection, which affects the concentration and duration of interferon in the blood on the one hand, and also correlates with the amount and duration of drug in the blood and liver, which is necessary for sustained inhibition of viral replication . Thus, the development of pegylated interferon has led to a significant improvement in the efficacy of interferon against HCV. Some differences in the efficacy of the two pegylated interferons also exist, and although the SVR rates were similar in the IDEAL study of pegylated interferon α-2b (1.5 μg/kg/week)/RBV and pegylated interferon α-2a (180 μg/week)/RBV, in a study including 12 studies comparing pegylated interferon α-2b/RBV and pegylated interferon α-2a/RBV in a clinical meta-analysis of randomized controlled studies showed a significant difference between pegylated interferon α-2b with an SVR of 41% and pegylated interferon α-2a with an SVR of 47% (p=0.04), with similar trends when only genotype 1 patients were analyzed for comparison, favoring pegylated interferon The relative risk for α-2a was 1.21 (95% CI: 1.03-1.42). Therefore, those who failed regular interferon therapy could be switched to PEG-IF therapy, and those who failed pegylated interferon α-2b (1.5 μg/kg/week) therapy were switched to pegylated interferon α-2a therapy, with the possibility of obtaining SVR, but those who failed pegylated interferon α-2a therapy should not be treated with pegylated interferon α-2b (1.5 μg/kg/week) retreatment.
The use of ribavirin was the second milestone in the antiviral treatment of chronic hepatitis C, further improving the antiviral treatment effect, thus forming the standard of care for pegylated interferon combined with RBV therapy. While the starting dose and maintenance dose of ribavirin can affect the rate of SVR acquisition, although the effective dose of ribavirin is 10.6 mg/kg/d, most scholars prefer to use a dose of 13-15 mg/kg/d in order to reduce relapse.
For patients who do not obtain the appropriate viral response at conventional doses during treatment, instead of waiting with an unchanging regimen to observe viral response at different time points, the treatment regimen should be changed promptly. Since the anti-HCV effect is related to the dose of interferon and ribavirin, the dose of both can be increased if tolerated, and even the dose of pegylated interferon alpha-2a has been increased from 180 to 360 μg. In contrast, in patients who cannot tolerate the conventional dose and have a viral response, symptomatic treatment should first be given for adverse drug reactions, and only if symptomatic treatment is still not effective in correcting the adverse drug reactions, the drug should be reduced according to the duration of treatment. shiffman ML et al. studied the effect of interferon or ribavirin dose reduction on SVR acquisition at different periods and showed that in the first 20 weeks of treatment, reducing the interferon dose will significantly affect the acquisition of SVR, while ribavirin dose has no significant effect on SVR as long as it is above 60% of the required amount, but discontinuation of ribavirin can lead to loss of opportunity to acquire SVR; while after 20 weeks, reducing interferon dose has no significant effect on SVR, and reducing ribavirin with guaranteed interferon dose also has no significant effect on SVR. The findings suggest that during the first 24 weeks of treatment, every effort should be made to ensure an effective interferon dose, and ribavirin should not be reduced to 60% of the required amount.
Caution is needed to shorten the course of therapy under standard PEG-IFN/RBV treatment.
Although the duration of treatment under standard treatment conditions is 24 weeks for genotype 2/3 and 48 weeks for genotype 1/4, it is difficult to be tolerated by some patients due to the side effects of the drug. Many studies have explored protocols and conditions for shortening the duration of treatment, and it has indeed been reported that in genotype 2/3 patients with low viral load at baseline (<4.0C8.0×105 IU/ml) who have achieved RVR on treatment, the duration of treatment can be to 16 weeks and up to 24 weeks in genotype 1 patients [38,39]. As the sensitivity of HCV RNA load detection reagents in China, especially in the primary level, is difficult to meet international requirements, clinical practice should try not to shorten the course of treatment. A study from Taiwan showed that 48 weeks of treatment was required for genotype 1 patients in China, regardless of whether RVR was obtained. Additional findings suggest that a longer course of treatment significantly reduces relapse rates and improves SVR rates, extending the course to 72 weeks in genotype 1 patients with DVR. Patients with genotype 2/3 without RVR should be treated for up to 48 weeks, and patients with DVR with negative factors should even be treated for up to 72 weeks. In patients with progressive liver fibrosis and cirrhosis, metabolic syndrome, insulin resistance and fatty liver, a shorter course is not recommended.
Clinical use of DAAs opens a new era of antiviral therapy for chronic hepatitis C.
Although PEG-IFN/RBV is the current standard of care for antiviral treatment of chronic hepatitis C, 30-40% of patients, especially those with genotype 1, still do not achieve SVR, so drugs with direct antiviral effects and their clinical applications have become a hot topic of research. Among them, telaprevir and boceprevir (both NS3/NS4 protease inhibitors) are approved by the US Food and Drug Administration and the European Medicines Agency for the clinical treatment of chronic hepatitis C. Large-scale clinical trials have also been conducted in patients with primary treatment and in patients who have failed previous treatment, respectively. Currently, DAA drugs are mainly used for the treatment of patients with genotype 1. The SVR of standard treatment for genotype 1 primary patients was increased from 38-44% to 63-75%, while the SVR of relapsed patients retreated by standard treatment was increased from 24-29% to 69-83% for patients who failed previous treatment, and the SVR of treatment non-responders retreated by standard treatment regimen was increased from 5% to 29-38%. Moreover, the treatment course could be shortened in patients who responded well. Although the use of DAAs significantly improves SVR, all require triple therapy with PEG-IFN/RBV, so for those patients who have difficulty tolerating the side effects of PEG-IFN/RBV, research and clinical use of DAAs drugs without interferon may still be awaited at this time. Patients who failed previous standard therapy were treated with PEG-IFN/RBV for another 4 weeks, and if HCV RNA decreased >1 log, then treated with PEG-IFN/RBV combined with boceprevir triple therapy for 12 weeks, to 32 weeks of PEG-IFN/RBV treatment (48 weeks in total), with an SVR of 82%, while those who had been treated with standard PEG-IFN/RBV the SVR was only 33%, a significant difference. It is evident that even in the era of triple therapy with PEG-IFN/RBV combined with DAAs, RGT treatment strategy is still needed and treatment should be stopped if HCV RNA load is still greater than 100 IU/ml at 12 weeks of treatment.
The antiviral treatment of chronic hepatitis C has gone through more than 10 years of history, which has established the status of PEG-IFN/RBV in the antiviral treatment of chronic hepatitis C and the principle of RGT, in which the viral genotype determines the basic course of antiviral treatment, and then it is important to determine the individualized course of treatment for each patient according to the viral response of the patient in the treatment. However, under the RGT principle, due attention should be paid to the limitations of our testing reagents in clinical application in order to maximize the chances of patients obtaining SVR. Although the antiviral treatment for patients with chronic hepatitis C in China is better than that for patients in Europe and the United States, there are still many patients, including special patients with cirrhosis and hemodialysis, whose antiviral treatment regimens require further research, and the clinical application of DAAs will certainly open a new era of antiviral treatment.