Interferon‐free therapy as the cause of white matter tracts and cerebral perfusion recovery in patients with chronic hepatitis C

The purpose of this study was to assess cerebral microstructural and perfusion changes in patients with chronic hepatitis C virus (HCV) infection before and after interferon‐free therapy, using advanced magnetic resonance (MR) techniques. Eleven HCV‐positive patients underwent diffusion tensor imaging (DTI) and perfusion‐weighted imaging (PWI) using a 1.5T MR unit, before and 24 weeks after completion of interferon‐free therapy. DTI fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained from 14 white matter tracts. PWI values of relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) were assessed from 8 areas, including basal ganglia, and cortical and white matter locations. In HCV‐positive patients therapy with ombitasvir, paritaprevir boosted with ritonavir and dasabuvir, with or without ribavirin, was scheduled. Cognitive tests were used to assess cognitive function. We found increased FA values after interferon‐free therapy compared to values obtained before treatment in HCV patients in almost all white matter tracts. We also observed elevated rCBV values in basal ganglia after therapy. There were significant correlations between improvement in the score of cognitive tests and increased FA values in both inferior fronto‐occipital fascicles and left posterior cingulum after treatment. Liver fibrosis regression in elastography, APRI and improvement in cognitive tests were observed. This is the first report of interferon‐free therapy as the cause of white matter tracts recovery as well as cerebral perfusion improvement in HCV‐infected patients, indicating better functioning of frontal lobes after interferon‐free treatment.     

Prevalence of thrombocytopenia among patients with chronic hepatitis C: a systematic review

Summary. Thrombocytopenia (TCP) is a haematological condition known to occur in chronically infected hepatitis C (HCV) patients and may interfere with diagnostic procedures, such as liver biopsy, because of risk of bleeding. It may also exclude patients from effective antiviral treatment. We conducted a systematic literature review of articles and conference abstracts, to assess the prevalence of TCP among those with HCV and to describe demographics, liver disease stage and treatment characteristics of these patients. Studies of individuals with confirmed chronic HCV infection were included in the review if the study had a clear definition of thrombocytopenia and a sample size of at least 50 subjects. The final selection included 27 studies (21 articles and six abstracts). The definitions of thrombocytopenia varied between studies and were based either on platelet counts, with threshold levels ranging between ≤100 × 10⁹ and ≤180 × 10⁹/L, or on criteria set in haematological guidelines. The prevalence of TCP ranged from 0.16% to 45.4% and more than half of the studies reported a TCP prevalence of 24% or more. Because of the different TCP definitions, heterogeneity in study design and insufficient data on study characteristics such as age, gender, HCV treatment rates and disease severity an overall summary estimate of TCP prevalence among patients with HCV was not feasible. However, the relatively large prevalence in the majority of the studies suggests that there may be a substantial number of HCV patients at risk of bleeding complications and reduced likelihood of successful HCV antiviral treatment .     

Intrapatient viral diversity and treatment outcome in patients with genotype 3a hepatitis C virus infection on sofosbuvir‐containing regimens

Treatment with the direct‐acting antiviral agent (DAA) sofosbuvir (SOF), an NS5B inhibitor, and velpatasvir (VEL), an NS5A inhibitor, demonstrates viral cure rates of ≥95% in hepatitis C virus (HCV) genotypes (GT) 1‐6. Here, we investigated intrapatient HCV diversity in NS5A and NS5B using Shannon entropy to examine the relationship between viral diversity and treatment outcome. At baseline, HCV diversity was lowest in patients infected with HCV GT3 as compared to the other GTs, and viral diversity was greater in NS5A than NS5B (P < .0001). Treatment outcome with SOF/VEL or the comparator regimen of SOF with ribavirin (RBV) was not correlated with baseline diversity. However, among persons treated with SOF/VEL, a decrease in diversity from baseline was observed at relapse in the majority virologic failures, consistent with a viral bottleneck event at relapse. In contrast, an increase in diversity was observed in 27% of SOF+RBV virologic failures. We investigated whether the increase in diversity was due to an increase in the transition rate, one mode of potential RBV‐mediated mutagenesis; however, we found no evidence of this mechanism. Overall, we did not observe that viral diversity at baseline influenced treatment outcome, but the diversity changes observed at relapse can improve our understanding of RBV viral suppression in vivo.     

Eight‐week regimen of antiviral combination therapy with peginterferon and ribavirin for patients with chronic hepatitis C with hepatitis C virus genotype 2 and a rapid virological response

Background: It remains unclear how we can shorten the treatment duration of antiviral combination therapy with peginterferon and ribavirin for patients with chronic hepatitis C virus (HCV) genotype 2 infection who achieved a rapid virological response (RVR). Aim: We compared the efficacy of antiviral combination therapy with peginterferon and ribavirin for 8 vs. 24 weeks for the treatment of patients with HCV genotype 2 infection and with RVR. Methods: Sixty‐one patients were enrolled. Serum HCV RNA was not detected at 4 weeks after the start of treatment in 32 patients with an RVR. These 32 patients were randomly assigned to 8‐week (n=15) or 24‐week (n=17) treatment regimens. Patients in the 8‐week group who relapsed underwent a 24‐week retreatment. Results: No significant difference in patient characteristics was observed between the 8‐ and the 24‐week treatment groups. A sustained virological response (SVR) was seen in five of 15 patients (33.3%) in the 8‐week treatment group and 14 of 17 (82.4%) in the 24‐week treatment group; the rate was significantly higher in the 24‐week treatment group (P=0.0140). Nine of 10 relapsed patients in the 8‐week treatment group underwent a 24‐week retreatment, and seven achieved an SVR. Conclusion: An 8‐week regimen of combination antiviral therapy with peginterferon and ribavirin yielded an increase in the relapse rate, indicating the limitation of a reduction of treatment below 12 weeks in patients with genotype 2, after RVR.     

Interferon‐α/β for treatment of chronic hepatitis C infection in the era of direct‐acting antiviral agents

Type I interferons (IFN‐α/β), with or without ribavirin, have been the only agents that can eradicate the hepatitis C virus (HCV). An IFN‐free regimen combining oral direct‐acting antiviral agents (DAA) will be approved soon for genotype 1 patients. Here, we discuss the role of IFN‐α/β in the forthcoming “era of DAA” with consideration of limitations and concerns about IFN‐free therapies. First, the therapeutic efficacy of first‐generation DAA varies among the different subtypes. While the rate of sustained virological response (SVR) is 60–90% among patients with genotype 1b, the rate often falls short of 50% in patients with genotype 1a. IFN and ribavirin can still be indicated for patients with genotype 1a as a platform for combination with DAA. Second, there is concern about the emergence of drug‐resistance resulting from inappropriate use of DAA. The clinical significance of pre‐existing resistant variants has not been elucidated. Drug resistance may affect the efficacy of next‐generation treatments. An IFN and ribavirin backbone in combination with DAA is an effective measure to prevent the emergence of drug resistance and/or to suppress pre‐existing resistant viruses. Third, it remains unknown whether the incidence of hepatocellular carcinoma (HCC) will be reduced in patients who achieve SVR with IFN‐free regimens. In contrast, there are many reports in Japan demonstrating the preventive effects of IFN on the development of HCC. When patients do not achieve SVR with first‐generation DAA, low‐dose IFN maintenance therapy is a treatment option until the next‐generation therapy with pan‐genotypic potency and high genetic barrier become available.     

不同直接抗病毒药物方案对基因1b型慢性丙型肝炎及代偿期丙型肝炎肝硬化临床结局的影响

目的探讨不同直接抗病毒药物(DAAs)对基因1b型慢性丙型肝炎(CHC)及丙型肝炎代偿期肝硬化(CLC)临床结局的影响。方法以2018年1月-2018年12月就诊于山西医科大学第一医院感染科门诊的115例基因型1b型CHC(n=91)及CLC(n=24)患者为研究对象。所有患者根据病情均采用DAAs抗病毒治疗,CHC患者中28例采用索磷布韦联合维帕他韦方案,21例采用艾尔巴韦格拉瑞韦片方案,16例采用奥比帕利联合达塞布韦方案,13例采用索磷布韦联合达拉他韦方案,13例采用索磷布韦联合利巴韦林方案;CLC患者中15例采用索磷布韦联合维帕他韦方案,4例采用艾尔巴韦格拉瑞韦片方案,5例采用索磷布韦联合达拉他韦方案。分析2组患者的肝功能复常率及病毒学应答率,并观察药物的不良反应。计量资料组间比较采用t检验,计数资料组间比较采用χ^2检验。结果90.4%的患者在治疗1周时获得超快速病毒学应答,98.2%的患者在治疗4周时获得快速病毒学应答,100%的患者在治疗12周时获得完全早期病毒学应答,100%的患者在治疗结束后12周获得持续病毒学应答;不同抗病毒治疗方案在治疗1周、4周时HCV RNA阴转率差异均无统计学意义(χ^2值分别为2.83、0.07,P值均>0.05)。不同抗病毒方案均可明显改善患者肝功能(ALT和AST复常率),不同组间疗效差异均无统计学意义(χ^2值分别为0.83、1.23,P值均>0.05)。DAAs治疗12周后,2组患者肾功能指标与治疗前相比未见有明显升高或降低,差异均无统计学意义(t值分别为1.32、0.56,P值均>0.05)。不良事件的发生率较低,恶心2例(1.74%),头晕、心悸、皮疹、溶血各1例(0.87%)。结论根据病情采用相应DAAs抗病毒方案治疗1b型患者,均可取得较好的病毒学应答率,肝功能改善显著、不良事件的发生率低。     

Adjuvant therapy used in conjunction with combination therapy for chronic hepatitis C improves sustained virus response rates in genotype 1 patients

Summary. Combination treatment with pegylated interferon (Peg‐IFN) and ribavirin remains the gold standard in the treatment of chronic hepatitis C. This therapy is limited by many side‐effects including anaemia, neutropenia and reduced quality of life. The use of adjuvant agents to reduce the frequency of dose reductions because of haematological side‐effects has been proven to be effective but there are few reports of what effect the use of these adjuvant therapies is having on sustained virological response (SVR). The aim of the study was to assess the clinical impact on sustained virological response of adjuvant therapies during combination therapy with Peg‐IFN and ribavirin for chronic hepatitis C. A total of 132 patients, 96 males, were included in the study. The overall SVR was 66.7%, with 50% of genotype 1/4/6 (n = 27/54) patients achieving SVR and 78.2% of genotypes 2/3. The overall SVR of the treatment naïve patients (83/121) was 68.6%. Fifty‐one of these patients were genotype 1 with 49.0% (25/51) of this group achieving SVR. The genotype 2/3 group of treatment naïve patients reached an SVR of 82.9% (58/70). Adjuvant therapy was used in 57 patients (43.8%). With the use of supportive adjuvant therapy, we achieved an overall SVR of 66.7% and in treatment naïve patients 68.6%. In genotype 1 patients, SVR rates of up to 46% have been reported in previous studies without the use of erythropoietin and granulocyte colony stimulating factor. We have demonstrated the SVR for genotype 1 can be improved to 50% overall.     

Direct antiviral treatment of chronic hepatitis C in heart transplant recipients

Direct‐acting antiviral agents (DAAs) are a safe and effective treatment for chronic hepatitis C (CHC). This may be particularly valuable for patients with severe comorbidities or baseline conditions, including non‐liver solid organ transplant. We report cases of two heart transplant recipients with CHC treated with DAAs (sofosbuvir and daclatasvir) achieving sustained virological response. Treatment was well tolerated and no relevant side effects were observed. The drug‐drug interactions and graft function were carefully monitored.     

The role of serum sphingolipids as potential biomarkers of non-response to direct acting antiviral therapy in chronic hepatitis C virus infection

Elimination strategies of chronic hepatitis C virus (HCV) infection aim to optimize the high antiviral potency of direct-acting antivirals (DAAs). Sphingolipids (SLs) constitute bioactive lipid compounds with a remarkable second messenger potential. SL levels associate with responsiveness to interferon treatment in HCV-patients, thus prompting the question whether failure to DAAs can be predicted by the serologic sphingolipidomic profile. Liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) was used to retrospectively quantify various sphingolipid metabolites in baseline serum samples of 97 chronic HCV patients with DAA failure compared with an age-matched cohort of 95 HCV-patients with sustained virological response (SVR). Sphingosine, sphinganine, sphingosine-1-phosphate (S1P) and sphinganine-1-phosphate (SA1P) serum concentrations were significantly upregulated at baseline in patients with DAA failure compared to patients with SVR. Similarly, GluC24:1Cer baseline levels were significantly upregulated in patients with DAA failure compared to the patients with SVR. However, GluC18Cer serum levels showed decreased baseline levels for patients with DAA failure compared to patients with SVR. In multivariate analysis sphinganine (OR 0.08494, CI 0.07393–0.9759, p = .021223), SA1P (OR 0.9818, CI 0.9653–0.9987, p = .034801), GluCerC18 (OR 1.0683, CI 1.0297–1.1104, p = .000786) and GluCer24:1 (OR 0.9961, CI 0.994–0.998, p = .000294) constituted independent predictors of treatment response. In conclusion, serum sphingolipid concentrations, in particular sphingosine, sphinganine and their derivatives S1P and SA1P as well as glucosylceramides may identify at baseline the minority of HCV patients with DAA failure. Serum sphingolipids could constitute additional biomarkers for national treatment strategies aiming to eliminate HCV infection.     

A 2-log drop in viral load at 1 month is the best predictor of sustained response in HCV patients with normal ALT: a kinetic prospective study

Summary.  The most reliable predictor of a sustained virological response in patients with persistently normal ALT has not been identified. We analysed 17 patients with genotype 1 chronic HCV who underwent therapy with pegylated interferon alfa 2b and ribavirin for 48 weeks. Two patients discontinued therapy within 28 days because of side effects and the remaining 15 patients were analysed in detail. An analysis of on treatment virological response using area under the receiver operating characteristic analyses showed that a 2 log drop in HCV RNA at day 28 was the best predictor of a sustained virological response and a failure to reduce viral load by 2 logs correctly identified patients with a low (<15%) probability of achieving a sustained virological response. Introduction of this early discontinuation rule in patients with normal ALT would allow nearly half of the patients to discontinue futile therapy at an early stage.     

Impact of direct‐acting antiviral agents on liver function in patients with chronic hepatitis C virus infection

Whilst the benefit of direct‐acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well‐accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon‐based therapy. Liver function was assessed by the albumin‐bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan = 99%, UK = 78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2 years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2‐3 years after interferon‐based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon‐based therapy suggests that failure to achieve SVR is associated with long‐term decline in liver function and, in contrast, patients who do achieve SVR can expect long‐term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course.     

Retreatment of patients with chronic hepatitis C,subtype 1b and cirrhosis,who failed previous direct‐acting antiviral therapy including first‐ and second‐generation NS5A inhibitors with ombitasvir/paritaprevir/ritonavir,dasabuvir + sofosbuvir + ribavirin

The use of direct‐acting antiviral agents (DAAs) in patients with chronic HCV genotype 1 infection results in sustained virologic response (SVR) rates of 95%‐97%, but 3%‐5% of patients experience virologic failure. We observed 17 patients infected with HCV subtype 1b who failed previous treatment with DAA, including 13 subjects (76.5%) with liver cirrhosis. Twelve subjects (70.6%) previously received NS5A inhibitors of the first generation (ledipasvir or daclatasvir) and five subjects (29.4%) – the second generation (velpatasvir). All patients were retreated with a combination of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D) with sofosbuvir (SOF) and ribavirin (RBV). We compared SVR₁₂ rates depending on fibrosis stage, presence of just single or double NS5A mutations (L31M/V/I and/or Y93H), and on the generation of previously used NS5A inhibitor. Observed SVR₁₂ rates were as follows: 94.1% (16/17 patients) overall; 100% in patients without cirrhosis (n = 4) vs 92.3% in those with cirrhosis (n = 13); 100% with single L31M/V/I or Y93H mutation (n = 7) vs 88.9% with double mutations (n = 9); 100% in patients who previously failed first generation (n = 12) vs 80.0% in those failed second‐generation NS5A inhibitors (n = 5). Retreatment with 3D + 0SOF + RBV was highly effective and safe in patients with chronic HCV GT1b infection who failed previous use of NS5A inhibitors. Fibrosis stage, baseline presence of NS5A RAS mutations and the generation of previously used NS5A inhibitors may impact the probability of achieving SVR₁₂, but statistical significance was not demonstrated in our small retrospective cohort. Further studies in a larger population are needed to confirm or not the predictive value of these baseline factors.     

Risk factors for the development of diabetes mellitus in chronic hepatitis C virus genotype 4 infection

Background and Aim:  A high occurrence of type 2 diabetes (T2D) in patients with chronic hepatitis C virus (HCV) infection has been reported in Kuwait and other countries. However, HCV genotype 4 has been underrepresented in all previous studies. Our aim was to investigate the viral and host risk factors associated with the development of T2D in patients with chronic hepatitis C genotype 4 infection in the absence of liver fibrosis and steatosis.
Methods:  The study population consisted of 181 HCV-positive patients and 170 control HCV-negative patients with T2D.
Results:  The prevalence of HCV-patients with T2D was 39.8%. There was no significant association of T2D with gender, nationality, obesity, HCV viral load, or antiviral therapy. Older age (≥ 50 years) and family history of diabetes were the only independent risk factor for T2D in HCV patients. However, the median age and the prevalence of obesity in HCV-positive patients with T2D were significantly lower than those in diabetic HCV-negative patients. By following-up HCV-patients receiving antiviral drugs, a significant decrease of fasting plasma glucose and glycosylated hemoglobin levels was observed in diabetic patients who achieved a sustained viral response (SVR).
Conclusions:  The risk factors associated with the development of T2D in the general population cannot alone account for the high prevalence of T2D obtained in chronic HCV genotype 4 infection. In the absence of liver fibrosis and steatosis, the improvement in glycemic control obtained in SVR patients may imply direct involvement of HCV in the development of T2D.