PEG-IFN α in combination with ribavirin (RBV) has become the standard of care for chronic hepatitis C (HC) [1-2]. People with genotype 2 or 3 infection can achieve a 50% sustained virologic response (SVR), and hepatitis C is therefore considered a “curable disease”, i.e., SVR with the above standard of care (patients with an SVR at the end of treatment and after 24 weeks of follow-up) peripheral blood HCV RNA is below 50 IU/ml or lower) [3]. However, under the current standard treatment regimen, some patients fail to achieve SVR; some patients with specific infections have lower SVR; meanwhile, HCV infection has insidious clinical manifestations and lacks specificity, and patients often develop until the late stage of the disease before they are diagnosed; in addition, some patients have other diseases in addition to HCV infection and become special patients. Therefore, the international progress on antiviral treatment for chronic hepatitis C mainly includes two aspects: on the one hand, optimization of existing treatment methods; on the other hand, development of novel treatment methods.
1.Optimization of treatment methods
The current consensus is to optimize the treatment approach by adjusting some key factors in the treatment. These factors include the dose and duration of PEG-IFNα and RBV in treatment, the baseline viral genotype and amount, and the response status in the early stage of treatment. Based on the presence or absence of these factors
Based on the presence or absence of these factors, the standard treatment approach was optimized as follows: 48 weeks of PEG-IFNα in combination with RBV for genotypes 1, 4, and 6, with early virologic response (EVR) measured at 12 weeks of treatment and continued for 48 weeks if viral load decreases by 2 log10; if viral load decreases by less than 2 log10, treatment can be stopped. For genotype 2 and 3 virus-infected patients given 24 weeks of PEG-IFNα in combination with RBV, EVR is not required to be measured at 12 weeks of treatment [1].
2, Refractory hepatitis C was first proposed to refer to chronic hepatitis C with co-infection with HIV [4], because the response rate to antiviral therapy in such patients is lower than in those without co-infection with HIV. With the advancement of chronic hepatitis C research and the progress made in the treatment of some specific patient groups, refractory hepatitis C can be understood in two ways [5-6]: on the one hand, patients who do not achieve SVR with standard therapy or who relapse after the end of standard therapy, which are typically refractory hepatitis C patients; on the other hand, patients who are predicted to have a possible post-treatment non-response based on their baseline characteristics or early treatment , such as men, older individuals (over 40 years), those with genotype 1 or 4 infection, those with high viral load, those of African descent, those with co-infection with HIV, those with intravenous drug addiction, those with poor compliance, those with high body mass index (body mass over 85 kg), those with metabolic syndrome and insulin resistance, and those with progressive liver fibrosis and cirrhosis [5]. For high viral load, an early definition was HCV RNA >2×106 copies/ml, and currently HCV RNA is considered to be (4-8) × 105 IU/ml. different clinical studies have used different thresholds, but what is certain
HCV RNA >8×105 IU/ml is considered high viral load. In addition, more in-depth studies are needed for these patients, including how to make full use of existing treatments, novel agents or new therapeutic drugs to improve SVR in order to reduce the occurrence of end-stage liver disease such as cirrhosis and hepatocellular carcinoma.
3. treatment of relapsed and non-responders Relapsed and non-responders are truly refractory hepatitis C patients who did not achieve a response after PEG-IFNα combined with RBV therapy or achieved a response at the end of therapy but relapsed at 6-month follow-up without achieving SVR. retreatment of these patients is currently focused on optimizing IFN-α-based treatment regimens [7]. If previous treatment with conventional IFN-α was unresponsive or relapsed, retreatment with PEG-IFNα combined with RBV increased the SVR rate from 8% to 42%.Poynard et al [8] treated such patients with PEG-IFN α-2b [1.5 μg/ (kg?week)] and RBV (800-1400 mg/d) for 48 weeks, with an overall Jensen et al [9] increased the dose of drug and prolonged the duration of treatment to improve SVR in those who did not respond to previous PEG-IFNα combined with RBV or relapsed; those who did not respond to previous PEG-IFNα-2b combined with RBV were given PEG-IFNα-2a ( 360 μg/week) for 12 weeks of induction followed by continuation of standard therapy to 72 weeks, or a high-dose induction for 12 weeks followed by maintenance of 48 weeks of therapy, or simply an extension of therapy to 72 weeks without high-dose induction. The results showed that the extended course was superior to high-dose induction, but the SVR rate was only 16% in the extended course group and 7% or 9% in the high-dose induction group. It is based on these studies that the clinical practice guideline for chronic hepatitis C published by the American College of Hepatology in 2009 [1] clearly states that those who have been treated with IFN-α in combination with or without RBV, or who have failed to respond or relapsed on PEG-IFN α alone, may be considered for reapplication of PEG-IFN α in combination with RBV, especially in patients with bridging fibrosis or cirrhosis; for those who have completed the PEG-IFN α combined with RBV full course of treatment without obtaining SVR, reapplication of PEG-IFN α combined with RBV is not recommended, even with a different type of PEG-IFN α. Therefore, the treatment of these patients must rely on specific targeted antiviraltherapy for hepatitis C (STAT-C), which has recently completed clinical studies. The newly developed telaprevir, a specific targeted inhibitor of the genotype 1 HCV protease, was reported at the 2008 American Liver Congress in a study of PEG-IFNα-2a in combination with RBV plus telaprevir in patients with refractory hepatitis C. The results showed that 73% of those who relapsed on prior therapy and 41% of those who did not respond to prior therapy had HCV RNA below detection at 12 weeks of therapy. HCV RNA was below detection level at 12 weeks of treatment [10].
level at 12 weeks of treatment [10]. In addition to telaprevir, the protease inhibitor boceprevir has now completed clinical phase 2 studies, and the protease inhibitors BI201335 and TMC435350 and the polymerase inhibitor R1626 are in clinical phase 2 studies. However, studies have shown that STAT-C does not yet have the basis for complete freedom from IFN-α therapy and may present new problems of drug resistance. 2009 European Liver Annual Meeting, Susser et al [11] reported a 4-year follow-up of people with resistance mutations after boceprevir treatment and found that resistance mutations can persist for a long time and that the proportion of mutant strains reached 4% to 80% in quasispecies. There are few relevant studies in large scale multicenter in China, and the population of refractory hepatitis C has to be further defined clearly. Moreover, telaprevir and boceprevir have not been clinically studied in our country. Therefore, we still need to do more work in controlling hepatitis C, especially refractory hepatitis C. At present, we should make full use of the available resources and protocols to obtain the highest possible SVR.
The initial treatment of genotype 1 virus-infected patients with genotype 1 virus is focused on optimizing existing regimens for on-treatment viral response, while STAT-C is used to significantly improve SVR over the next 3 to 5 years or longer, as the SVR rate after 48 weeks of standard antiviral therapy in genotype 1 virus-infected patients is significantly lower than that after 24 weeks of standard antiviral therapy in genotype 2 or 3 virus-infected patients. standard antiviral therapy. If these patients (mainly lentiviral responders) do not achieve an EVR on treatment (viral load decline log10 or below detection level at 12 weeks of treatment), the SVR can be improved by extending the PEG-IFN regimen. it should be noted, however, that even if the SVR is improved by extending the regimen, the final SVR is still unsatisfactory. The SVR rates of PEG-IFN α-2a treatment in patients with primary genotype 1 viral infection were: 9% (72-week course) and 17% (48-week course); the relapse rates were: 40% (72-week course) and 64% (48-week course), respectively [12]. Therefore, standard treatment relying only on optimized PEG-IFN α in combination with RBV has limited efficacy. A treatment that has significantly improved SVR in genotype 1 virus-infected patients in recent years is STAT-C, and more established regimens include the addition of telaprevir or boceprevir to PEGIFN α combined with RBV. telaprevir added to the first 12 weeks of 24-week PEG-IFN α-2a combined with RBV treatment in patients with primary genotype 1 virus infection that resulted in SVR rates of 61% (US study) and 69% (European study). Although the total duration of therapy was shortened, SVR rates remained higher than those of standard treatment at 48 weeks (41% in the US study and 46% in the European study) [13-14]. Patients with primary treatment of genotype 1 viral infection treated with boceprevir in combination with PEG-IFNα-2b in addition to RBV had an SVR rate of 55% at 28 weeks, while the control group without boceprevir had an SVR rate of only 33% at 48 weeks [15].
5, Treatment of patients with cirrhosis
The 2007 Asia-Pacific Hepatology Society Hepatitis C Expert Consensus [2] and the 2009 Clinical Practice Guidelines for Chronic Hepatitis C published by the American College of Hepatology [1] both
believe that liver transplantation should be considered for the treatment of decompensated hepatitis C cirrhosis, but there is no consensus on whether to give antiviral therapy. For compensated
cirrhosis, SVR, biochemical response and histological response can be achieved with either plain IFN or PEG-IFNα in combination with RBV therapy. One study showed that the normal IFN
IFN group, 90 μg PEG-IFN group, and 180 μg PEG-IFN group showed SVR rates of 8%, 15%, and 30% at 72 weeks, respectively [16]. Although the SVR rate was relatively low in patients with cirrhosis compared with non-cirrhotic patients, it still delayed the progression of cirrhosis in these responders and relatively reduced the incidence of hepatocellular carcinoma [17]. However, the occurrence of adverse events should be closely monitored during the treatment of patients with compensated cirrhosis. In decompensated cirrhosis, if antiviral therapy is given, it is recommended to be performed in an experienced liver center and it should be clear that antiviral therapy is based on reducing reinfection after liver transplantation and not on obtaining SVR. most patients with decompensated cirrhosis already have granulocytopenia, thrombocytopenia, and anemia before treatment, and antiviral therapy can exacerbate these symptoms, thus making treatment very risky. However, it should also be noted that recent data have shown the feasibility of antiviral therapy in decompensated cirrhosis.Iacobellis et al [18] gave PEG-IFNα-2b [1.0 μg/(kg?week)] in combination with standard doses of RBV for 24 weeks in patients with decompensated cirrhosis (including all genotypes) and achieved an overall SVR rate of 19.7%, with genotypes 2 and 3 The SVR rate was 43.5% for those with genotypes 2 and 3, and 7% for those with genotypes 1 and 4. Most of our chronic hepatitis C patients were infected in the late 1980s and early 1990s, and currently, many of them have entered the cirrhotic stage or even the decompensated stage. Therefore, decompensated hepatitis C
cirrhotic patients deserve to be explored, especially the main difficulties of antiviral therapy and the methods that can overcome them must be clarified
and timing. Through joint research, further studies should be conducted on the patients who can be treated, the course of treatment, the dosage and adjustment of drugs, and the related adverse effects and treatment, in order to achieve the best benefit and the least harm, to create conditions for liver transplantation, or to improve the prognosis and quality of life of patients who cannot undergo liver transplantation and prolong their survival.
6, antiviral therapy in patients with fatty liver, metabolic syndrome, and insulin resistance Hepatic steatosis is an independent risk factor for failure of antiviral therapy in patients with chronic hepatitis C and is not related to viral genotype [19]; obesity is also a factor causing low response to antiviral therapy in chronic hepatitis C. Obese chronic hepatitis C patients with a body mass index of more than 30 kg/m2 have a higher chance of obtaining SVR than non-obese patients 1/4 of non-obese patients [20].A multicenter, randomized, double-blind, placebo-controlled study reported at the 2008 American Liver Annual Meeting randomized 123 patients with genotype 1 viral infection with insulin resistance on primary IFN to 2 groups, one of which added metformin 425 mg, 3/d to PEG-IFNα-2a combined with RBV and switched to 850 mg, after 4 weeks 3/d until the end of treatment (48 weeks); the other group was given conventional treatment with PEG-IFN α-2a combined with RBV. By ITT and PP analysis, there was no significant difference in SVR rate between the 2 groups, but insulin resistance index was reduced by 1.8 and 0.6, respectively, with significant differences. In subgroup analysis, a significant difference in SVR rates was found in female patients in the 2 groups, 57.7% and 28.6%, respectively [21]. The prevalence of fatty liver and metabolic syndrome in our country is significantly higher than it has been in the past. At present, the relationship between fatty liver and HCV infection and the prevalence of fatty liver in patients with chronic hepatitis C are not well understood and must be further clarified, and the impact on antiviral therapy must be observed so as to form an effective antiviral treatment plan.
7. Diagnosis and treatment of children with HCV infection HCV-infected mothers can passively transmit their own anti-HCV to the fetus via the placental umbilical cord during delivery. Therefore, newborns of HCV-positive mothers should not be diagnosed with hepatitis C infection solely because of anti-HCV positivity, but should be tested for anti-HCV after 18 months of age or for HCV RNA at 1 to 2 months of age. based on the available evidence-based medical evidence, pediatric patients over 2 years of age should only receive IFN-α treatment with PEG-IFNα-2b [60 μg/(m2?week)] in combination with RBV [15 mg/(kg?d)] for 48 weeks.8 Diagnosis and treatment of patients with co-infection with HIV
Because HIV and HCV infections share a common transmission route, all HIV-infected patients should receive anti-HCV testing, especially those with a history of shared injecting equipment.
All HIV-infected patients should be tested for anti-HCV, especially those who have a history of sharing injecting equipment. HCV core antigen testing is expected to be used for early diagnosis of anti-HCV negative patients in the next 3 to 5 years. Treatment of HIV co-infected patients with HCV should begin by identifying which infection is more severe, and treating hepatitis C if the severity of liver disease and the likelihood of a treatment response outweigh the consequences of adverse events. The initial regimen for treatment is PEG-IFN alpha in combination with RBV for 48 weeks. For patients treated with zidovudine or desoxymethyldeoxyinosine, they should be switched to other nucleoside analogues to avoid aggravating liver damage [1].
9, Treatment of organ transplant patients with histologic evidence after liver transplantation may be considered for PEG-IFNα combined with or without RBV antiviral therapy, but should be closely monitored. Antiviral therapy for liver transplant patients with chronic hepatitis C end-stage liver disease is divided into four conditions: pre-transplant therapy, prophylaxis, early post-transplant therapy, and delayed post-transplant therapy [9]. Pre-transplantation treatment is mainly for primary patients with mild decompensation or low MELD scores, and IFN-α is used in a progressive dosing regimen to reduce HCV RNA below detectable levels before transplantation; prophylaxis uses hepatitis C globulin and monoclonal antibodies to HCV envelope region 2, but no significant results have been obtained; early post-transplantation treatment is further divided into antiviral therapy within 8 weeks after transplantation and 2-6 months after transplantation The former is for those with high-risk progressive disease, while the latter is for those with predicted progressive disease; delayed post-transplant treatment is for patients with progressive disease or severe tissue and biochemical alterations to reduce the risk of disease progression [22]. Except for liver transplantation, antiviral therapy should not be given to patients with solid organ transplants such as heart, lung, or kidney, because IFN-α will promote graft rejection and lead to graft inactivation. IFN-α therapy may be considered only in the presence of fibrous sideroblastic hepatitis, when the benefits of antiviral therapy outweigh the adverse consequences.
In summary, antiviral therapy for chronic hepatitis C has made important gains in improving SVR, delaying and reducing the progression of chronic hepatitis C to end-stage liver disease, improving survival
However, new therapeutic approaches have created new problems such as drug resistance. Recently, four major projects related to hepatitis C have been established in the 11th Five-Year Plan, which will lead to more standardized treatment and control of chronic hepatitis C in China. This will contribute to the formation of our own data and the establishment of norms.