The success in the development of targeted therapeutics for chronic hepatitis C is evident. three new direct antivirals (DAAs) were launched in Europe in the first half of 2014, in response to which the European Academy of Hepatology (EASL) published new guidelines for hepatitis C. Prior to the introduction of DAAs, pegylated interferon Peg-IFN in combination with ribavirin (RBV) as an indirect antiviral agent was the standard regimen for the treatment of CHC for a long time.
Whereas DAAs are designed to directly target hepatitis C virus (HCV) proteins, some of which are nonstructural, drugs that have been or are expected to be approved include.
Sofosbuvir (SOF): HCV RNA-dependent RNA polymerase nucleotide analog inhibitor, the first approved pan-genetic antiviral drug, known as the “super bomb” of hepatitis C treatment.
Simeprevir (SMV): 2nd generation non-structural protein (NS) 3/4A inhibitor for the treatment of HCV genotyping (GT) I and 4 HCV infections. Polymorphs are common in GT1a infections, which are resistant to SMV in vitro and thus have a decreased response. It is recommended that patients with GT1 HCV infection be screened for Q80K and that other drugs be considered if present.
(iii) Daclatasvir (DCV): NS5A inhibitor, effective in GTI, GT2 and GT3 HCV infections and more likely to be used in interferon-free (IFN) regimens.
I. Choice of CHC treatment regimen
The 2014 EASL guidelines provide a wide range of treatment options for all primary and treated CHC patients based on data from current clinical trials of DAAs, mainly divided into two categories: IFN/RBV-based regimens and IFN-free regimens. The regimens were selected based on HCV genotyping/subtypes, degree of liver fibrosis, previous treatment response, and the presence of amino acid polymorphisms associated with DAAs. In addition, IFN and RBV tolerance or non-tolerance are also factors to consider for regimen selection.
GT1 and 4: In general, GTI and 4 are refractory CHC, and most common GTI types in China are subtype 1b. GT4 types are commonly found in Egypt and other Arab countries, and their efficacy is the same as that of GT1 CHC, so treatment regimens, precautions and monitoring are roughly the same. There are six treatment options available (Table 1): the first three are based on IFN/RBV, with a triple regimen of SOF, SMV and DCV on top of IFN/RBV, respectively; the other three are IFN-free regimens, which are two DAAs drugs combined with or without RBV treatment. Without considering economic issues, the most effective diphasic regimen is Peg-IFNα+RBV+SOF, and the most attractive of the IFN-free regimens may be SOF plus SMV or DCV (combined or not combined with RBV).
(1) Regimen 1: Peg-IFNα+RBV (dose of 1000 mg/d for patients weighing <75 kg and 1200 mg/d for those weighing ≥75 kg, RBV dose is consistent across all regimens without further elaboration) combined with SOF (400 mg/d) for 12 weeks of treatment. The sustained response (SVR) rate for this regimen in primary patients was 89%, with SVR rates of 92% for subtype la, 82% for subtype Ib, and 96% for type 4, with significantly higher SVR in patients without cirrhosis than in patients with cirrhosis (92% vs. 80%). This regimen is the preferred IFN+RBV-based regimen, but there is no evidence-based medical rationale for its use in the treatment of patients with primary non-responsive or relapsing GTlb CHC.
(2) Option 2: Peg-IFNα+RBV+SMV (150 mg/d) therapy. Studies have shown that SMV triple therapy is significantly more effective than the standard regimen alone in patients with GTI-type primary and treated relapses.
However, there are several noteworthy points in applying this treatment regimen.
① CHC patients with GTla subtype treated with positive NS3 protease sequence Q80K substitution detected by direct sequencing method at baseline were not treated with this combination regimen, as the study showed that SVR was 85% in CHC patients with GTlb subtype, 84% in those with negative GTIa subtype Q80K substitution and only 58% in those with positive, while SVR was 89 percent.
(ii) The degree of baseline fibrosis in patients significantly affected SVR: 84% in patients with fibrosis (F) grade 0-2 on the liver biopsy scoring system (METAVIR), 73% in grade F3, and only 60% in grade F4.
(iii) All patients were treated with triple therapy for the first 12 weeks, with patients with initial and relapsed GTI (including liver fibrosis) continuing Peg-IFNα+RBV therapy until 24 weeks, and patients with previous partial response or non-response in GTI (including liver fibrosis) and GT4 requiring Peg-IFNα+RBV therapy until 48 weeks. The study showed that retreatment SVR was 70% in relapsed patients with subtype Ib, 78% in those negative for Q80K substitution with subtype La and only 47% in those positive; retreatment SVR was 69,7% in previous partial responders and 43,6% in non-responders; while for GT4 patients, SVR was 86% in relapsed patients, 100% in previous partial responders and 75% in non-responders. patients was 75%.
The treatment regimen was adjusted by monitoring HCV RNA levels during treatment, and treatment was stopped immediately if HCV RNA was ≥25 IU/ml at 4, 12 or 24 weeks.
(3) Regimen 3: Peg-IFNα+RBV+DCV (60 mg/d) for 24 weeks. This regimen is only used for patients with GT4 and 1b subtypes, and there is no evidence of evidence of disease based medicine for those with la subtypes. The regimen was 100% SVR for primary GT4 and 87% SVR for subtype 1b, compared to 58% for patients with la. All patients were treated with triple therapy for the first 12 weeks, and those with HCV RNA ≥25 IU/ml at 4 weeks and those with detectable HCV RNA at 10 weeks continued with triple therapy until 24 weeks.
SOF in combination with SMV or DCV is the preferred regimen for IFN-free, and whether to combine with RBV depends on the patient’s previous treatment response (relapse, partial response, or no response).
(4) Regimen 4: SOF (400 mg/d) in combination with SMV (150 mg/d) for 12 weeks. The study showed that this regimen was used to treat 96% and 93% SVR in previously non-responding F0-F1 patients (with or without RBV) and 100% and 93% SVR in previously non-responding F3-F4 patients (with or without RBV), respectively, and 100% SVR in primary F3-F4 patients, with the addition of RBV. RBV difference was also not statistically significant. patients with GTla subtype need to be tested for the presence of Q80K positivity if this regimen is used.
(5) Regimen 5: SOF (400 mg/d) combined with DCV (60 mg/d) treatment for 12 weeks in primary patients and 24 weeks in retreatment patients. to and no significant difference between genetic subtypes (la/1b). The latter (non-responders and with cirrhosis) had SVRs of 100% and 95% at 24 weeks of treatment (with or without RBV), respectively, so the guidelines still recommend adding RBV for patients (with or without liver fibrosis) who have not responded to previous treatment.
(6) Option 6: In the absence of SMV or DCV, SOF (400 mg/d) in combination with RBV for 24 weeks is still an option, which is the next best option in the IFN-free regimen. The SVR was only 68% in primary GTI-type patients and 10% in treated patients treated for 12 weeks.
2. GT2, 3, 5 and 6 types: Compared to GT1 and 4 types, the remaining GT types (2, 3 and 5 and 6 types) have better treatment efficacy and are still acceptable even with standard regimens in the absence of DAAs. In contrast, patients with GT type 2, especially without cirrhosis, can also achieve high SVR with the IFN-free regimen.
(1) GT2: The most recommended regimen for patients with GT2 CHC is the no-IFN regimen: SOF (400 mg/d) combined with RBV for 12 weeks, with extended courses up to 16 or 20 weeks recommended for patients with liver fibrosis, especially in patients who have failed treatment.
The study showed that the SVR reached 95% at 12 weeks of treatment in primary patients, rising to 97% in patients without liver fibrosis, and increased from 60% to 93% in patients with liver fibrosis at 16 weeks of treatment. However, in patients who had failed previous standard regimens, especially those with liver fibrosis, the SVR was 73% if SOF combined with RBV was continued for 16 weeks. Therefore, it is recommended that 12 weeks of Peg-IFNα+RBV+SOF treatment can achieve an SVR of 96%.
(2) GT3 type: Although both GT2 and GT3 types are considered to be relatively better types for treatment, the relative efficacy of GT3 patients is less favorable compared to GT2 type. Therefore, the most recommended treatment regimen is IFN-based triple therapy (the primary recommended regimen for homozygous type 1/4): its SVR is 90%, and even in the presence of cirrhosis, its SVR is still as high as 83%. The secondary recommended regimen is the same as the IFN-free regimen for GT2 type but with an extended efficacy up to 24 weeks: SOF combined with RBV for 24 weeks achieves an SVR of 94% in patients with primary treatment without liver fibrosis, 92% in those with primary liver fibrosis, 87% in patients with treated liver fibrosis, and 60% in patients with treated liver fibrosis. This shows that GT3 type requires an extended course of therapy to achieve the same efficacy as GT2 type if the IFN-free regimen is used.
For patients with RBV-associated anemia, SOF (400 mg/d) combined with DCV (60 mg/d) is recommended in the IFN-free regimen for 12 weeks for primary patients and 24 weeks for repeat patients. Both in vitro and in vivo trials have shown that DCV is effective in treating genotype 3 CHC, with SVR of 89% in primary patients treated with the above regimen.
(3) GT5 and 6: Patients with GT5 and 6 CHC exist in the southern region of China as well as in Southeast Asia, and the optimal treatment regimen is not known. Although in the NEUTRINO phase III study, one case of GT5 and six cases of GT6 patients treated with SOF combined with Peg-IFN and RBV obtained SVR, the recommended grade is B1 due to the small number of cases; for intolerant patients, the IFN-free regimen is the same as GT3, but there is no relevant literature to support it, so the recommended grade is C2.
II. Treatment monitoring and program adjustment
Efficacy monitoring is required during the course of treatment. Patients receiving either triple therapy for 12 or 24 weeks should be tested for HCVRNA at baseline, 4 and 12 weeks (or 24 weeks), and 12 or 24 weeks after the end of treatment; patients treated with the no-IFN regimen should be tested for HCVRNA at baseline, 2 (compliance assessment), 4, 12 or 24 weeks (end of treatment), and 12 or 24 weeks after the end of treatment; and all of the above assessment time nodes should use a real-time PCR method with a lower limit of detection of HCV RNA levels <15 IU/ml.
With the introduction of combination therapy with DAAs, the guideline adds the principle of termination (futility). This is based on the fact that HCV RNA viruses, with their rapid replication and lack of corrective activity of polymerase, can generate viral mutants in the viral genome, and primary mutants that are not sensitive to DAAs can be generated before treatment, while viral mutants can also appear in patients with virological breakthrough or non-response during treatment, thus affecting antiviral efficacy. Therefore, if HCV RNA is not rapidly suppressed with DAAs, the discontinuation principle should be applied and DAAs should be discontinued to avoid cross-resistance with subsequent drug use. This principle applies to all triple therapy and should be discontinued if HCV RNA is ≥25 IU/ml at week 4, 12 or 24.
Patients treated with Peg-IFNα+RBV should be evaluated for clinical safety at each follow-up visit. Assessment of IFN- and RBV-related adverse effects (e.g., peripheral cytopenia) is required at weeks 2 and 4 of treatment and at 4-week intervals. renal function should be monitored regularly in patients treated with SOF, and patients treated with SMV may experience rash and elevated bilirubin.
Individualized treatment
The individualized treatment in this article is mainly for patients with compensated cirrhosis, patients with indications for liver transplantation (decompensated cirrhosis and hepatocellular carcinoma) and special populations. It is worth noting that
① If there are no contraindications to treatment, all should be treated with antiviral therapy, and IFN-free regimens are preferred;
②Treatment with RBV combined with SOF under close monitoring in an experienced center is recommended first.
③In HCV combined with human immunodeficiency virus (HIV) or hepatitis B virus (HBV) infection, the indications for treatment are the same as for HCV infection alone, and the treatment regimen is the same as for those without HIV or HBV combination;
④Patients on hemodialysis and those with hemoglobinopathies should preferably not be treated with regimens with RBV.
IV. Summary
There are no DAAs available in China, but two phase III clinical trials have been conducted, namely SMV in combination with primary treatment of GT1 patients and DCV in combination with intolerant GT1b patients, with the latter having an SVR of more than 80% according to data from a Japanese malefactor study. Although all-oral DAAs are a great benefit for CHC patients, their recent widespread use in Chinese patients is still difficult due to their high price and drug resistance. Patients with both IL-28B dominant genotype and refractory subtype 1b HCV genotype have better outcomes with standard regimens, and relapsed patients are more likely to be treated with an irregular initial regimen (not combined with RBV or using a regular IFN). Therefore, the current treatment of CHC should not only wait for the combination of DAAs, but should be standardized and monitored by existing means as much as possible, and patients who really need to be treated by combination of DAAs or IFN-free regimens in the future are mostly refractory CHC patients.