Sofosbuvir,velpatasvir and voxilaprevir combination for the treatment of hepatitis C

Introduction: The advent of direct-acting antiviral (DAA) treatments for chronic hepatitis C virus (HCV) infection has dramatically increased rates of cure. However, there remain difficult-to-treat populations, including patients with genotype 3 infection and cirrhosis, and limited salvage treatment options for those that have failed first-line DAA therapy.

Areas covered: This is a review of the preclinical and clinical development of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX), an interferon-free, oral, once daily, pangenotypic treatment for chronic HCV infection. All relevant literature from 2015 through June of 2017 is included.

Expert commentary: Voxilaprevir, a second-generation HCV protease inhibitor, in combination with the already approved combination of sofosbuvir and velpatasvir, was evaluated in the POLARIS trials and found to be a safe and effective regimen. Patients with prior DAA treatment failure, genotype 3, cirrhosis and/or unfavorable resistance profiles all achieved cure rates of 96% or greater. The most distinctive role for this potent regimen may prove to be as a salvage regimen for patients who have failed previous DAA therapy.     

Resistance characterization of ledipasvir and velpatasvir in hepatitis C virus genotype 4

HCV genotype 4 (GT4) has often been overlooked in drug development, even though it infects ~20 million people worldwide. Ledipasvir/sofosbuvir and sofosbuvir/velpatasvir were highly efficacious in GT4 HCV‐infected patients from GS‐US‐337‐1119 and GS‐US‐342‐1138. Here, we characterize the resistance profile of ledipasvir (LDV) and velpatasvir (VEL) in patients with GT4 HCV infection. NS5A deep‐sequencing was performed for 454 patients infected with HCV GT4 at baseline, including 44 patients enrolled in GS‐US‐337‐1119 and 116 patients enrolled in GS‐US‐342‐1138, and at relapse for patients with virologic failure. LDV and VEL susceptibilities of 56 patient isolates were determined. In GS‐US‐337‐1119, SVR12 rates were 100% for all subtypes except 4b and 4r. Phenotypic assessment of 56 HCV NS5A patient isolates from various GT4 subtypes indicated that LDV had high potency for the common subtypes 4a/d, and subtypes 4c/f/k/l/m/n/o/p/r/t despite the presence of resistance‐associated substitutions (RASs). For the rare GT4b, LDV median EC₅₀ was higher, but with a broad range of individual values. Importantly, all GT4b isolates tested had 2‐4 NS5A RASs, some including Y93H. Similarly, the 2 GT4r infected patients who had virologic relapse had rare triple RASs. Reversion of these substitutions to the consensus residue significantly increased LDV susceptibility. In GS‐US‐342‐1138, all patients achieved SVR12, regardless of their subtype or presence of RASs. In vitro data confirmed that VEL is potent against all GT4 isolates tested. LDV and VEL are potent antiviral drugs, estimated to be effective against >95% and >99%, respectively, of GT4 HCV isolates.     

Sofosbuvir plus simeprevir for the treatment of genotype 1 chronic hepatitis C: a review of evidence

Introduction: Sofosbuvir (SOF) with simeprevir (SIM) combination was the first interferon-free regimen that reached optimal results in terms of sustained viral response (SVR).

Areas covered: A systematic review of the scientific literature concerning the effects that the SOF/SIM combination had on hepatitis C genotype 1 patients yielded 771 references. After the revision process, four clinical trials and 15 observational studies met the inclusion criteria; in total, these studies involved 5,766 patients. The SVR ranged from 67% to 100% depending on the patients’ viral subtype and cirrhosis status. Adverse effects were common, but treatment discontinuation related to drug toxicity occurred in less than 5% of cases.

Expert commentary: The SOF/SIM combination exhibits efficacy and tolerability profiles that are similar to those of the other available interferon-free combinations used for non-cirrhotic genotype 1b patients. Meanwhile, for patients with advanced cirrhosis or genotype 1a, this approach cannot be considered a routine treatment option due to the unsatisfactory results.     

Global Real-World Evidence of Sofosbuvir/Velpatasvir as a Highly Effective Treatment and Elimination Tool in People with Hepatitis C Infection Experiencing Mental Health Disorders

Hepatitis C virus (HCV) is prevalent in people with mental health disorders, a priority population to diagnose and cure in order to achieve HCV elimination. This integrated analysis pooled data from 20 cohorts in seven countries to evaluate the real-world effectiveness of the pangenotypic direct-acting antiviral (DAA) sofosbuvir/velpatasvir (SOF/VEL) in people with mental health disorders. HCV-infected patients diagnosed with mental health disorders who were treated with SOF/VEL for 12 weeks without ribavirin as part of routine clinical practice were included. The primary outcome was sustained virological response (SVR) in the effectiveness population (EP), defined as patients with an available SVR assessment. Secondary outcomes were reasons for not achieving SVR, characteristics of patients with non-virological failures, adherence, and time from HCV RNA diagnosis to SOF/VEL treatment initiation. A total of 1209 patients were included; 142 did not achieve an SVR for non-virological reasons (n = 112; 83 lost to follow-up, 20 early treatment discontinuations) or unknown reasons (n = 30). Of the 1067 patients in the EP, 97.4% achieved SVR. SVR rates in the EP were ≥95% when stratified by type of mental health disorder and other complicating baseline characteristics, including active injection drug use and antipsychotic drug use. Of 461 patients with data available in the EP, only 2% had an adherence level < 90% and 1% had an adherence level < 80%; all achieved SVR. Patients with mental health disorders can be cured of HCV using a well-tolerated, pangenotypic, protease inhibitor-free SOF/VEL regimen. This DAA allows the implementation of a simple treatment algorithm, with minimal monitoring requirements and fewer interactions with central nervous system drugs compared with protease-inhibitor DAA regimens.     

Eight weeks of sofosbuvir/velpatasvir for genotype 3 hepatitis C in previously untreated patients with significant (F2/3) fibrosis

Twelve weeks sofosbuvir/velpatasvir (SOF/VEL) is a highly effective pan‐genotypic regimen for hepatitis C. Phase 2 data suggest 8 weeks of treatment may be sufficient for previously untreated noncirrhotic patients with genotype 3 (GT3) infection. To maximize the number of patients potentially cured within a fixed treatment budget, we elected to treat such patients locally eligible for treatment (F2/3), with 8 weeks of SOF/VEL. By local protocol, treatment‐naive patients with F2 (LSM > 6.9kPa < 9.5kPa) or F3 fibrosis (≥9.5kPa < 12.5kPa) were eligible for 8‐week SOF/VEL treatment. Patients commencing treatment before 1 Oct 2017 were identified from the Scottish HCV database. Baseline and treatment outcome data obtained. Ninety patients were included for analysis (72 (80%) male, mean age 45 (IQR ± 8.4), 28 (31.1%) F3 fibrosis). Opioid agonist therapy (OAT) was prescribed in 82 (91.1%) patients. Of 49 patients attending Glasgow city Alcohol and Drug Services, 27 (55.1%) had evidence of recent drug use (< 3 months) including 8 (16.3%) with self‐reported intravenous drug use. On an intention‐to‐treat basis, SVR rates were 86/90 (95.6%, 95% CI 89.0‐98.8). Excluding those who prematurely discontinued treatment (n = 4), died prior to SVR testing (n = 1) or whom experienced reinfection (n = 1), per‐protocol SVR rate was 84/84 (100%, 95% CI 95.7‐100.0). In conclusion, eight‐week SOF/VEL is highly effective in treatment‐naive GT3 patients with significant fibrosis. This offers a non‐protease inhibitor‐based 8‐week regimen which may be useful for complex drug interactions or where time‐limited opportunity for treatment. In limited resource settings, reduction in drug acquisition costs may help achieve progress towards the goal of HCV elimination.     

The Novel Finding of Dynamic Change in eGFR Up to One Year after End of Treatment in HCV-Infected Patients Receiving Sofosbuvir and Velpatasvir

Background: The results of long-term renal evolution in HCV-infected patients using sofosbuvir and velpatasvir (SOF/VEL), with or without ribavirin (RBV), are lacking. Aims: We evaluated the renal safety for HCV-infected patients receiving SOF/VEL. Methods: Between 1 June 2019 and 6 July 2020, we included 594 HCV-infected patients receiving SOF/VEL +/− RBV for 12 weeks in Taiwan. Viral eradication rate (defined by sustained virological response at week 12 post-treatment; SVR12) and changes to renal function were considered. Results: SVR12 was achieved in 99.3% (590/594) upon per-protocol analysis. Patients saw improved hepatobiliary function and fibrosis after the start of SOF/VEL therapy. For renal function, those with baseline estimated glomerular filtration rate (eGFR) ≥ 60 (mL/min/1.73 m²) experienced transient on-treatment reduction in renal function that improved upon ending treatment, but recurrent eGFR degradation during one-year follow-up. The use of RBV (OR = 5.200, 95% CI: 1.983–13.634, p = 0.001) was a significant risk factor at SVR24, while diabetes mellitus (OR = 2.765, 95% CI: 1.104–6.922, p = 0.030) and the use of RBV (OR = 3.143, 95% CI: 1.047–9.435, p = 0.041) were identified as significant risk factors of worsening renal function at SVR48. SOF/VEL did not worsen renal function among those with stage 4–5 chronic kidney disease (CKD) who were not receiving dialysis. Conclusions: A trend of decline in eGFR at 1 year after SOF/VEL treatment was observed among diabetic patients with baseline eGFR ≥ 60 (mL/min/1.73 m²) and concomitant use of RBV. The close monitoring of renal function is warranted. Further study should be conducted in order to weigh the risks and benefit of RBV.     

Sofosbuvir/Velpatasvir Plus Ribavirin Combination Therapy for Patients with Hepatitis C Virus Genotype 1a, 2a,or 3b after Glecaprevir/Pibrentasvir Therapy Failed

Glecaprevir/pibrentasvir (GLE/PIB) is a pan-genotype anti-hepatitis C virus (HCV) therapy with high efficacy and safety. However, evidence supporting retreatment following failure of the GLE/PIB regimen is limited. We herein report 3 non-cirrhotic cases involving two men aged 51 and 58 years old and a woman aged 68 years old infected with HCV genotype 1a, 2a, and 3b respectively who failed anti-HCV therapies including GLE/PIB therapy. With combination therapy of sofosbuvir/velpatasvir plus ribavirin (SOF/VEL+RBV) for 24 weeks, all 3 patients had achieved a sustained viral response (SVR) at 24 weeks after completing treatment. SOF/VEL+RBV therapy was effective for retreatment of HCV after failure of GLE/PIB therapy.     

Autoantibodies and hepatitis C virus genotypes in chronic hepatitis C patients in Estonia

AIM: To determine the prevalence of several autoantibodies in chronic hepatitis C patients, and to find out whether the pattern of autoantibodies was associated with hepatitis C virus (HCV) genotypes. METHODS: Sera from 90 consecutive patients with chronic hepatitis C were investigated on the presence of anti-nuclear (ANA), anti-mitochondrial (AMA), anti-smooth muscle (SMA), anti-liver-kidney microsomal type 1 (LKMA1), anti-parietal cell (PCA), anti-thyroid microsomal (TMA), and anti-reticulin (ARA) autoantibodies. The autoantibodies were identified by indirect immunofluorescence. HCV genotypes were determined by a restriction fragment length polymorphism analysis of the amplified 5' noncoding genome region. RESULTS: Forty-six (51.1%) patients were positive for at least one autoantibody. Various antibodies were presented as follows: ANA in 13 (14.4%) patients, SMA in 39 (43.3%), TMA in 2 (2.2%), and ARA in 1 (1.1%) patients. In 9 cases, sera were positive for two autoantibodies (ANA and SMA). AMA, PCA and LKMAI were not detected in the observed sera. HCV genotypes were distributed as follows: 1b in 66 (73.3%) patients, 3a in 18 (20.0%), and 2a in 6 (6.7%) patients. CONCLUSION: A high prevalence of ANA and SMA can be found in chronic hepatitis C patients. Autoantibodies are present at low titre (1:10) in most of the cases. Distribution of the autoantibodies show no differences in the sex groups and between patients infected with different HCV genotypes.     

Failure on voxilaprevir,velpatasvir, sofosbuvir and efficacy of rescue therapy

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Sofosbuvir plus ledipasvir in combination for the treatment of hepatitis C infection

Sofsobuvir is the first-in-class NS5B nucleotide inhibitor to be launched as a treatment for the hepatitis C virus (HCV). Its viral potency, pan genotypic activity and high barrier to resistance make it the ideal candidate to become a backbone for several IFN-free regimens. Ledipasvir is a NS5A inhibitor with multi genotypic activity but modest barrier to resistance. The once-daily fixed-dose combination of sofosbuvir plus ledipasvir is the first-in-market single-tablet regimen for the treatment of hepatitis C infection. Recent data demonstrated that this FDC alone, or in combination with ribavirin, is able to achieve HCV cure of at least 90% or more among genotype 1,4, 5 and 6 patients. This combination appears to be suboptimal in genotype 3 patients and other direct acting antiviral combinations with sofosbuvir will help to fulfill this gap in the near future. The safety profile of the fixed dose combination is good. Resistance is not an issue with sofosbuvir but may be a significant issue with regards to ledipasvir for those rare individuals who harbor baseline HCV NS5A resistance–associated variants that conferred a high resistance level. The rational for using FDCs and the available clinical data are reviewed.     

索非布韦治疗慢性丙型肝炎的研究进展

近几年慢性丙型肝炎的治疗发生了新的变化,直接抗病毒药物治疗活动性丙型肝炎显示出强大的作用,即使是难治性丙型肝炎也能出现较高的持续病毒学应答。其中索非布韦(SOF)以其抗病毒疗程短,应答率高,甚至对于某些丙型肝炎基因型患者可免干扰素治疗的优势脱颖而出。介绍了SOF的作用机制、临床应用现状以及主要不良反应,指出了其在难治性丙型肝炎患者中的应用前景。     

索磷布韦和维帕他韦联合利巴韦林治疗基因2、3型慢性丙型肝炎患者近期疗效和耐受性观察*

目的 研究应用索磷布韦/维帕他韦联合利巴韦林治疗基因2、3型慢性丙型肝炎(CHC)患者的近期疗效及耐受性。方法 2018年6月～2019年4月收治的58例基因2、3型CHC患者,采用抽签随机法分为两组,每组29例。给予对照组利巴韦林联合干扰素α-2b治疗,观察组接受索磷布韦/维帕他韦联合利巴韦林治疗,两组均持续治疗3个月。采用实时荧光定量聚合酶链反应法检测血清HCV RNA载量,采用基因芯片法检测HCV基因分型。结果 观察组快速病毒学应答(RVR)和早期病毒学应答(EVR)率分别为72.4%和89.7%,显著高于对照组的44.8%和65.5%(P＜0.05);在治疗4周末,观察组外周血白细胞计数为(5.8±2.1)×10⁹/L,显著高于对照组【(3.7±1.9)×10⁹/L,P＜0.05】;在治疗12周结束时,观察组外周血白细胞和血小板计数分别为(3.4±0.4)×10⁹/L和(99.60±24.2)×10⁹/L,均显著高于对照组【分别为(2.9±0.9)×10⁹/L和(82.01±14.8)×10⁹/L,P＜0.05】;两组不良反应发生率比较差异无统计学意义(P＞0.05),均未出现终止治疗情况。结论 应用索磷布韦/维帕他韦联合利巴韦林治疗基因2、3型CHC患者近期临床疗效确切,安全性较好,值得进一步观察。     

索磷布韦维帕他韦治疗慢性丙型肝炎患者疗效和安全性观察:一项单中心真实世界回顾性分析

目的 回顾性分析索磷布韦维帕他韦(SOF/VEL)联合利巴韦林(RBV)治疗慢性丙型肝炎(CHC)患者真实世界研究(RWS)的疗效和安全。方法 2018年5月～2020年4月初治/PR经治的CHC患者32例和代偿期丙型肝炎肝硬化(CHC-CLC)患者36例,接受SOF/VEL治疗12 w,失代偿期丙型肝炎肝硬化(CHC-DLC)或合并肝细胞癌(HCC)患者31例,接受SOF/VEL联合利巴韦林(RBV)治疗12 w。部分患者合并存在高血压、糖尿病、肿瘤和慢性乙型肝炎。采用RT-PCR法检测HCV基因型(GTs)。结果 本组HCV 感染患者以GT 2a(55.6%)和GT1b(34.3%)为主;CHC、CHC-CLC和CHC-DLC患者早期病毒学应答(EVR4)分别为90.6%、86.1%、83.9%,治疗结束病毒学应答(EOT)均为100.0%,CHC组和CHC-CLC组SVR12和SVR24均为100.0%,CHC-DLC组 SVR12和SVR24均为93.5%,三组间EVR4、EOT、SVR12、SVR24均无显著性差异(P>0.05);所有患者SVR12和SVR24均为97.8%,除GT3b型外其他GTs感染患者SVR12和SVR24均为100.0%;三组血生化学应答率分别为87.5%、83.3%和74.2%;本组总体不良反应(AE)发生率为12.1%,无严重AE或因AE停药和死亡事件发生。结论 应用SOF/VEL或联合RBV治疗CHC或相关的肝硬化患者,无论何种基因型感染,均有良好的效果,且安全。     

In vitro resistance profile of hepatitis C virus NS5A inhibitor velpatasvir in genotypes 1 to 6

Velpatasvir is a pan‐genotypic hepatitis C virus (HCV) NS5A inhibitor, which is used with sofosbuvir for treatment of infection with HCV genotypes 1‐6. In vitro resistance studies were performed to characterize NS5A changes that might confer reduced velpatasvir susceptibility in vivo. Resistance selection studies using HCV replicon cells for subtypes 1a, 1b, 2a, 2b, 3a, 4a, 5a and 6a identified NS5A resistance‐associated substitutions (RASs) at nine positions, most often 28M/S/T, 31F/I/M/P/V and 93D/H/N/S. In subtype 1a, RASs were selected at positions 31 and/or 93, while in subtype 1b, replicons with two or more RASs at positions 31, 54 or 93 were selected. Y93H was selected in subtypes 1a, 1b, 2a, 3a and 4a. In subtype 5a or 6a, L31P or P32L/Q was selected, respectively. Velpatasvir susceptibility of 358 replicons from genotypes 1 to 6 containing one or more NS5A RASs was also evaluated. The majority (63%) of subtypes 1a and 1b single RAS‐containing replicons retained susceptibility to velpatasvir (<2.5‐fold change in EC₅₀). High levels of resistance to velpatasvir were observed for six single mutants in subtype 1a, including M28G, A92K, Y93H/N/R/W and for one mutant, A92K, in subtype 1b. Most single mutants in subtypes 2a, 2b, 3a, 4a and 5a displayed low levels of reduced velpatasvir susceptibility. High‐level resistance was observed for C92T and Y93H/N in subtype 2b, Y93H/S in 3a, and L31V and P32A/L/Q/R in 6a, and several double mutants in these subtypes. Overall, velpatasvir maintained activity against most common RASs that are known to confer resistance to first‐generation NS5A inhibitors.     

Current therapy for hepatitis C

Introduction Pegylated interferon alfa in combination with ribavirin has been established as standard therapy for chronic hepatitis C virus (HCV) infection with sustained virologic response rates of 54–63%. The duration of therapy depends on the HCV genotype with currently 48 weeks for genotype 1 and 24 weeks for genotypes 2 and 3. Results and discussion The probability of sustained virologic response is very low (<1–2%) in genotype-1-infected patients without a 2-log decline of HCV RNA concentration after 12 weeks of therapy, and treatment can therefore be discontinued early. Conclusion Efficient treatment of the multiple side-effects of interferon-based antiviral therapy is essential in order to improve compliance, prevent dose reduction or early discontinuation and therefore enhance the probability of sustained response. Future developments of interferon-based therapy aim at the individualisation of the duration of therapy according to the kinetics of viral reduction. Furthermore, direct antiviral drugs, which are currently under investigation in phase I/II clinical trials, will fundamentally expand the treatment options of HCV infection in the next few years.     

《丙型肝炎防治指南(2015年更新版)》要点解读

本文对我国 2015 年更新版的《丙型肝炎防治指南》中丙型肝炎的流行病学、诊断、抗病毒治疗的时机选择、抗 HCV 药物种类、治疗方案的选择、特殊人群的抗病毒治疗及监测随访等方面进行解读,以期更好地应用于临床实践.     

Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis C in the United States

Hepatitis C virus (HCV) RNA status and HCV genotype have become important tools in the diagnosis and monitoring of therapy in chronic HCV infection. To establish a database with respect to HCV genotype and serum HCV RNA concentrations in chronic hepatitis C patients in the United States, we analysed 6807 chronic hepatitis C patients who had HCV RNA and HCV genotype tests conducted at a central laboratory. The HCV RNA concentration cut-off for the lower 25th percentile of this population (low titre) was 0.9 × 10⁶ copies ml^–1. The median HCV RNA concentration was 3.5 × 10⁶ copies ml^–1 and the cut-off for the upper 25th percentile (high titre) was 5 × 10⁶ copies ml^–1. Male patients had a median HCV RNA concentration of 3.9 × 10⁶ copies ml^–1, which was significantly higher than the median HCV RNA level for females (2.75 × 10⁶ copies ml^–1; P  < 0.001). HCV genotype 1 was detected in 73% of patients; genotype 2 in 14%; genotype 3 in 8%; mixed genotype in 4%; and genotypes 4, 5 and 6 with a frequency of < 1%. Patients from the Northeast, Southeast and Midwest had significantly ( P  < 0.001) more infections with genotype 1 than patients from the Western and Southern regions. African–American patients were more likely to be infected with genotype 1 when compared with Caucasian, Hispanic or Asian Pacific Islanders ( P  < 0.001). Patients infected with HCV genotype 1 and mixed HCV genotypes had significantly higher serum HCV RNA concentrations when compared with HCV genotypes 2 and 3 ( P  < 0.001 for all comparisons).