Favouring modulation of circulating lipoproteins and lipid loading capacity by direct antiviral agents grazoprevir/elbasvir or ledipasvir/sofosbuvir treatment against chronic HCV infection

ObjectiveLipid homoeostasis is disturbed in patients with HCV infection. Direct-acting antiviral agent (DAA) treatment eradicates chronic HCV viraemia, but the dynamics of lipid components remain elusive. This study investigates the clinical manifestation and mechanistic relevance of plasma triglyceride (TG), cholesterol (Chol), lipoproteins and apolipoproteins (apos) after DAA treatment.DesignTwenty-four patients with chronic genotype 1 (GT1) HCV treated with elbasvir/grazoprevir or ledipasvir/sofosbuvir for 12 weeks, and followed-up thereafter, were recruited. Their TG, Chol, apoAI and apoB levels were quantified in plasma samples and individually fractionated lipoprotein of various classes. Liver fibrosis was evaluated using the FIB-4 Score. The TG and Chol loading capacities were calculated with normalisation to apoB, which represents per very low density lipoprotein (VLDL) and LDL particle unitResultsDAA treatment achieved a sustained virological response rate of 91.7% and reduced the FIB-4 Score. Relative to the baseline, the plasma TG level was reduced but the Chol level increased gradually. Plasma apoB levels and apoB/apoAI ratio were transiently downregulated as early as the first 4 weeks of treatment. The TG and Chol loading capacities in VLDL were elevated by ~20% during the period of DAA treatment and had steadily increased by 100% at follow-up. Furthermore, the TG-to-Chol ratio in VLDL was increased, while the ratio in LDL was reduced, indicating an efficient catabolism.ConclusionThe DAA treatment of patients with chronic hepatitis C might lead to efficient HCV eradication and hepatic improvement concomitantly evolving with favouring lipoprotein/apo metabolisms.

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Virus Elimination by Direct-Acting Antiviral Agents Impacts Glucose Homeostasis in Chronic Hepatitis C Patients

Frontiers in Endocrinology ◽

10.3389/fendo.2021.799382 ◽

2022 ◽

Vol 12 ◽

Author(s):

Chun-Han Cheng ◽

Chia-Ying Chu ◽

Huan-Lin Chen ◽

I-Tsung Lin ◽

Chia-Hsien Wu ◽

...

Keyword(s):

Glucose Homeostasis ◽

Antiviral Agents ◽

Hcv Infection ◽

Treatment Experience ◽

Factors Associated ◽

Direct Acting Antiviral ◽

Chronic Hcv Infection ◽

Hcv Genotype 1 ◽

Chronic Hcv ◽

Direct Acting

Background and AimsChronic hepatitis C virus (HCV) infection is associated with dysregulation of glucose homeostasis, including insulin resistance (IR) and type 2 diabetes. However, independent risk factors associated with IR in chronic HCV-infected patients have not been detailly elucidated. Previous data regarding the impact of HCV elimination by direct-acting antiviral agents (DAAs) on glucose homeostasis is insufficient and controversial. This study aimed to analyze the independent factors associated with IR and to evaluate the changes in glucose homeostasis in chronic HCV-infected patients treated with DAAs therapies.MethodsWe screened 704 patients with chronic HCV infection who underwent treatment with interferon-free DAAs. Patients’ baseline characteristics, biochemical and virological data were collected. The outcome measurements were their IR and β-cell function assessed by the homeostasis model assessment (HOMA) method at baseline and 12-weeks post-treatment.ResultsHigh IR (HOMA-IR ≥ 2.5) was observed in 35.1% of the patients. Multivariable logistic regression analysis revealed that body mass index (BMI) >25 kg/m2, treatment experience, elevated baseline levels of alanine aminotransferase (ALT) and triglyceride, as well as Fibrosis-4 score >3.25 were independently associated with high IR. In patients who achieved sustained virological response (SVR), no significant change in mean HOMA-IR was observed from baseline to 12-weeks post-treatment (2.74 ± 2.78 to 2.54 ± 2.20, p = 0.128). We observed a significant improvement in β-cell secretion stress from 121.0 ± 110.1 to 107.6 ± 93.0 (p = 0.015). Subgroup analysis revealed that SVR was associated with a significant reduction in mean HOMA-IR in patients with baseline HOMA-IR ≥ 2.5 (5.31 ± 3.39 to 3.68 ± 2.57, p < 0.001), HCV genotype 1 (3.05 ± 3.11 to 2.62 ± 2.05, p = 0.027), and treatment experience (4.00 ± 3.37 to 3.01 ± 2.49, p = 0.039).ConclusionsThere were several independent factors associated with IR in patients with chronic HCV infection, including obesity, treatment experience, high serum ALT and triglyceride levels, as well as advanced hepatic fibrosis. After viral elimination by DAAs, we observed a significant reduction in mean HOMA-IR in patients with baseline high IR, HCV genotype 1, and treatment experience.

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The efficacy and safety of direct-acting antiviral agents in patients with chronic HCV infection and UGT1A1*28 polymorphism

Clinical Microbiology and Antimicrobial Chemotherapy ◽

10.36488/cmac.2020.1.71-80 ◽

2020 ◽

Vol 22 (1) ◽

pp. 71-80

Author(s):

S.P. Lukashyk ◽

I.A. Karpov ◽

M.G. Siniauskaya ◽

N.G. Danilenko ◽

L.A. Anisko ◽

...

Keyword(s):

Liver Cirrhosis ◽

Antiviral Agents ◽

Hcv Infection ◽

Efficacy And Safety ◽

Svr12 Rate ◽

Direct Acting Antiviral ◽

Chronic Hcv Infection ◽

Chronic Hcv ◽

Direct Acting ◽

Direct Acting Antiviral Agents

Objective. To determine the efficacy and safety of direct-acting antiviral agents (DAA) in patients with chronic HCV infection and UGT1A1*28 polymorphism. Materials and Methods. An open-label, non-randomized, observational study to assess efficacy and safety of DAA in patients (n = 143) with chronic hepatitis C (CHC) and liver cirrhosis and UGT1A1*28 polymorphism was performed. A total of 139 patients with chronic HCV infection were included in the efficacy analysis (absence of HCV RNA in blood by PCR) by the rate of sustained virologic response at week 12 (SVR12). Results. The SVR12 rate in patients with CHC and HCV-CP was 92.5% and 87.9%, respectively (p = 0.508), regardless of the presence of UGT1A1*28 polymorphism. The SVR12 rate in patients with chronic HCV infection and (TA)7/(TA)7 was 84.8%, with (TA)6/(TA)7 – 92.2% compared with (TA)6/ (TA)6 – 90,5% (p = 0.518). The rate of SVR12 in patients with CHC and (TA)7/(TA)7 or (TA)6/(TA)7 was 80% and 95%, respectively, with (TA)6/(TA)6 – 95.2%. The rate of SVR12 in patients with liver cirrhosis and (TA)7/(TA)7 or (TA)6/(TA)7 was 92.3% and 87.5%, respectively, with (TA)6/(TA)6 – 85.7%. The rate of SVR12 in patients with 12- and 24-week treatment duration was 88.2% and 96.6%, respectively (p = 0.30). As many as 96.2% of patients with the previous treatment with interferon and ribavirin had SVR12 compared to 88.5% of patients who have not previously taken antiviral drugs (p = 0.486). Grade 1 adverse events (AE) occurred in 24% of patients with chronic HCV infection treated with DAA; two patients developed Grade 4 AE. Conclusions. The treatment with DAA was shown to be effective and safe in patients with chronic HCV infection and UGT1A1*28 polymorphism.

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Additional Inhibition of Wnt/β-Catenin Signaling by Metformin in DAA Treatments as a Novel Therapeutic Strategy for HCV-Infected Patients

Cells ◽

10.3390/cells10040790 ◽

2021 ◽

Vol 10 (4) ◽

pp. 790

Author(s):

Dong Lin ◽

Venu Reddy ◽

Hanadi Osman ◽

Adriana Lopez ◽

Ali Riza Koksal ◽

...

Keyword(s):

Antiviral Agents ◽

Hcv Infection ◽

Novel Therapy ◽

Direct Acting Antiviral ◽

Chronic Hcv Infection ◽

Gsk 3Β ◽

Chronic Hcv ◽

Signaling Activation ◽

Direct Acting

Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/β-catenin signaling activation due to the inhibition of GSK-3β activity via serine 9 phosphorylation (p-ser9-GSK-3β) leading to stable non-phosphorylated β-catenin. Immunohistochemical staining demonstrated the upregulation of both β-catenin and p-Ser9-GSK-3β in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of β-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/β-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3β-mediated β-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/β-catenin signaling for HCV-infected patients.

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Case 21

Oxford Case Histories in Infectious Diseases and Microbiology ◽

10.1093/med/9780198846482.003.0021 ◽

2020 ◽

pp. 137-142

Author(s):

Will Irving

Keyword(s):

Antiviral Agents ◽

Virologic Response ◽

Hcv Infection ◽

Direct Acting Antiviral ◽

Chronic Hcv Infection ◽

Chronic Hcv ◽

Direct Acting ◽

End Stage ◽

Hcv Testing ◽

Direct Acting Antiviral Agents

Chronic hepatitis C (HCV) infection may be completely asymptomatic until the patient presents with complications of end-stage liver disease. Hence, anti-HCV testing should be performed on any patient with risk factors, which includes a raised alanine aminotransferase. Following diagnosis of chronic HCV infection, it is essential to know the genotype of the infecting virus, and whether or not the patient has underlying cirrhosis, as both of these factors will be important in determining the optimal therapeutic regimen. Direct-acting antiviral agents target 3 different viral non-structural proteins. The success of these drugs in achieving sustained virologic response (SVR) in well over 90% of patients in clinical trials has ended the era of interferon-based therapy for this infection. Therapy for most patients comprises one co/multiply-formulated tablet taken orally per day for 8 or 12 weeks.

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Statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor)-based therapy for hepatitis C virus (HCV) infection-related diseases in the era of direct-acting antiviral agents

F1000Research ◽

10.12688/f1000research.7970.2 ◽

2016 ◽

Vol 5 ◽

pp. 223 ◽

Cited By ~ 1

Author(s):

Sara Sobhy Kishta ◽

Reem El-Shenawy ◽

Sobhy Ahmed Kishta

Keyword(s):

Clinical Trials ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Antiviral Agents ◽

Antiviral Agent ◽

Viral Clearance ◽

Hcv Infection ◽

Direct Acting Antiviral ◽

Direct Acting ◽

Direct Acting Antiviral Agents

Recent improvements have been made in the treatment of hepatitis C virus (HCV) infection with the introduction of direct-acting antiviral agents (DAAs). However, despite successful viral clearance, many patients continue to have HCV-related disease progression. Therefore, new treatments must be developed to achieve viral clearance and prevent the risk of HCV-related diseases. In particular, the use of pitavastatin together with DAAs may improve the antiviral efficacy as well as decrease the progression of liver fibrosis and the incidence of HCV-related hepatocellular carcinoma. To investigate the management methods for HCV-related diseases using pitavastatin and DAAs, clinical trials should be undertaken. However, concerns have been raised about potential drug interactions between statins and DAAs. Therefore, pre-clinical trials using a replicon system, human hepatocyte-like cells, human neurons and human cardiomyocytes from human-induced pluripotent stem cells should be conducted. Based on these pre-clinical trials, an optimal direct-acting antiviral agent could be selected for combination with pitavastatin and DAAs. Following the pre-clinical trial, the combination of pitavastatin and the optimal direct-acting antiviral agent should be compared to other combinations of DAAs (e.g., sofosbuvir and velpatasvir) according to the antiviral effect on HCV infection, HCV-related diseases and cost-effectiveness.

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Hepatic resection for two giant hepatocellular carcinoma after oral direct-acting antiviral therapy: Is there a relationship?

Journal of Solid Tumors ◽

10.5430/jst.v8n2p32 ◽

2018 ◽

Vol 8 (2) ◽

pp. 32 ◽

Cited By ~ 1

Author(s):

Mohamed Abdel Wahab ◽

Ahmed Shehta ◽

Mahmoud Ali

Keyword(s):

Hepatocellular Carcinoma ◽

Antiviral Drugs ◽

Hcv Infection ◽

Dramatic Improvement ◽

Direct Acting Antiviral ◽

Increased Risk ◽

Chronic Hcv Infection ◽

Chronic Hcv ◽

Direct Acting ◽

The Relationship

Introduction: Direct-acting antiviral drugs have been recently introduced for management of chronic hepatitis C virus (HCV) patients. Those medications have achieved a dramatic improvement of sustained virologic response (SVR) reaching almost 90%. However, reports regarding the increased risk of occurrence or recurrence of hepatocellular carcinoma (HCC) in chronic HCV patients who achieved SVR after direct-acting antiviral drugs are controversial.Methods: We report two cases of giant HCCs complicating chronic HCV infection after direct-acting antiviral drugs-based therapies and were managed by major hepatic resection.Results: Two male patients with chronic HCV infection received several regimens oral direct acting antiviral drugs with a SVR for 3 and 6 months, respectively. They complained of progressive right hypochondrial pain and abdominal enlargement. Two large HCCs were diagnosed (16.2 cm * 17.6 cm * 16.9 cm, and 18 cm * 13 cm * 16.5 cm in dimensions) with markedly elevated serum alpha feto-protein (36,000 and 7,000 ng/ml, respectively). Due to the presence of adequate residual liver volume, the decision was to proceed for surgical resection. Central hepatectomy and extended right hemi-hepatectomy were performed, respectively. Patients had smooth postoperative course and were discharged after 10 and 9 days, respectively.Conclusion: The relationship between direct-acting antiviral drugs and HCC is controversial. Those cases add support to the accumulating literature suggesting the relationship of HCC development in chronic HCV patients receiving direct-acting antiviral drugs. Further prospective studies with adequate long term follow up are needed to prove or disprove this relationship.

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