Restrictions for reimbursement of interferon-free direct-acting antiviral drugs for HCV infection in Europe

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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Direct-acting antiviral drugs improve the female sexual burden associated with chronic HCV infection

Expert Review of Anti-infective Therapy ◽

10.1080/14787210.2019.1682551 ◽

2019 ◽

Vol 17 (11) ◽

pp. 919-926

Author(s):

Esam Elshimi ◽

Neamat Sakr ◽

Wesam Morad ◽

Noha Ezzat Mohamad ◽

Imam Waked

Keyword(s):

Antiviral Drugs ◽

Hcv Infection ◽

Direct Acting Antiviral ◽

Chronic Hcv Infection ◽

Chronic Hcv ◽

Direct Acting

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Remdesivir and Ledipasvir among the FDA-Approved Antiviral Drugs Have Potential to Inhibit SARS-CoV-2 Replication

Cells ◽

10.3390/cells10051052 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1052

Author(s):

Rameez Hassan Pirzada ◽

Muhammad Haseeb ◽

Maria Batool ◽

MoonSuk Kim ◽

Sangdun Choi

Keyword(s):

Antiviral Drugs ◽

Effective Concentration ◽

Nonstructural Proteins ◽

Rna Dependent Rna Polymerase ◽

Direct Acting Antiviral ◽

Rapid Spread ◽

Half Maximal Effective Concentration ◽

Dynamics Simulations ◽

Direct Acting ◽

Transcription And Replication

The rapid spread of the virus, the surge in the number of deaths, and the unavailability of specific SARS-CoV-2 drugs thus far necessitate the identification of drugs with anti-COVID-19 activity. SARS-CoV-2 enters the host cell and assembles a multisubunit RNA-dependent RNA polymerase (RdRp) complex of viral nonstructural proteins that plays a substantial role in the transcription and replication of the viral genome. Therefore, RdRp is among the most suitable targets in RNA viruses. Our aim was to investigate the FDA approved antiviral drugs having potential to inhibit the viral replication. The methodology adopted was virtual screening and docking of FDA-approved antiviral drugs into the RdRp protein. Top hits were selected and subjected to molecular dynamics simulations to understand the dynamics of RdRp in complex with these drugs. The antiviral activity of the drugs against SARS-CoV-2 was assessed in Vero E6 cells. Notably, both remdesivir (half-maximal effective concentration (EC50) 6.6 μM, 50% cytotoxicity concentration (CC50) > 100 µM, selectivity index (SI) = 15) and ledipasvir (EC50 34.6 μM, CC50 > 100 µM, SI > 2.9) exerted antiviral action. This study highlights the use of direct-acting antiviral drugs, alone or in combination, for better treatments of COVID-19.

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Direct-Acting Antivirals and Organ Transplantation: Is There Anything We Can’t Do?

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa420 ◽

2020 ◽

Vol 222 (Supplement_9) ◽

pp. S794-S801

Author(s):

Matthew R Kappus ◽

Cameron R Wolfe ◽

Andrew J Muir

Keyword(s):

Organ Transplantation ◽

The United States ◽

Virologic Response ◽

Hcv Infection ◽

Solid Organ ◽

Direct Acting Antiviral ◽

Transplant Candidates ◽

Direct Acting ◽

High Sustained Virologic Response ◽

Waitlist Mortality

Abstract The opioid epidemic has resulted in an increase in organ donors with hepatitis C virus (HCV) infection in the United States. With the development of direct-acting antiviral regimens that offer high sustained virologic response rates even in the setting of immunosuppression after transplantation, these HCV-viremic organs are now being offered to transplant candidates with or without preexisting HCV infection. Strategies for HCV treatment with HCV-viremic organs have included delayed and preemptive approaches. This review will discuss key studies in the different solid organ transplants, recent reports of adverse events, and ethical and regulatory considerations. The efficacy of current HCV therapies has created this important opportunity to improve survival for patients with end-organ failure through greater access to organ transplantation and decreased waitlist mortality rate.

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The occurrence of thrombotic thrombocytopenic purpura during treatment of HCV with direct-acting antiviral agents

african journal of gastroenterology and hepatology ◽

10.52378/kxkq8987 ◽

2018 ◽

Vol 1 (1) ◽

pp. 1-9

Author(s):

Amr Hanafy ◽

◽

Waseem Seleem ◽

Salem Mohamed ◽

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Hemolytic Anemia ◽

Peripheral Blood Smear ◽

Hcv Infection ◽

Severe Thrombocytopenia ◽

Direct Acting Antivirals ◽

Thrombocytopenic Purpura ◽

Direct Acting Antiviral ◽

Chronic Hcv ◽

Direct Acting

Background and aim Experts have reported thrombocytopenia linked to chronic liver disease in up to 70% in patients with advanced fibrosis and portal hypertension. Thrombotic thrombocytopenic purpura (TTP) occurrence with HCV infection is a rare and life-threatening event. We aimed to investigate the cause of disturbed conscious level, acute hemolytic anemia, and severe thrombocytopenia in a male patient with chronic HCV and under treatment with direct-acting antivirals. Case report: Development of severe thrombocytopenia, acute hemolytic anemia, neurological symptoms in the form of fits and coma in a 32- year- old man with chronic HCV infection after one week of treatment with direct-acting antivirals (sofosbuvir 400mg PO daily, and daclatasvir 60 mg PO daily). Brain CT was normal, with a negative Coombs test and the presence of schistocytes in the peripheral blood smear. The patient presentation was suggestive of thrombotic thrombocytopenic purpura (TTP). Conclusion: This is a case of TTP after one week of direct-acting antiviral drugs despite the safety profile of these medications. Studying the pathophysiology of TTP after DAAs needs more clarifications.

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Direct-acting antiviral agents for HCV infection affecting people who inject drugs

Nature Reviews Gastroenterology & Hepatology ◽

10.1038/nrgastro.2017.106 ◽

2017 ◽

Vol 14 (11) ◽

pp. 641-651 ◽

Cited By ~ 80

Author(s):

Jason Grebely ◽

Behzad Hajarizadeh ◽

Gregory J. Dore

Keyword(s):

People Who Inject Drugs ◽

Antiviral Agents ◽

Hcv Infection ◽

Direct Acting Antiviral ◽

Direct Acting ◽

Direct Acting Antiviral Agents

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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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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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Hepatitis C Virus Infection and Renal Disorders

Journal of Renal and Hepatic Disorders ◽

10.15586/jrenhep.2019.43 ◽

2019 ◽

Vol 3 (1) ◽

pp. 1-14

Author(s):

Maurizio Salvadori ◽

Aris Tsalouchos

Keyword(s):

Hepatitis C Virus ◽

Renal Transplantation ◽

Hepatitis C ◽

Sustained Virologic Response ◽

Virologic Response ◽

Antiviral Drugs ◽

Renal Diseases ◽

Renal Disorders ◽

Direct Acting Antiviral ◽

Direct Acting

Hepatitis C virus (HCV) infection is frequently associated with extrahepatic disorders, among which renal diseases are frequent. This article highlights the most frequent HCV-associated renal disorders, the impact of HCV infection on chronic renal disease and renal transplantation, and the role of current direct-acting antiviral therapies. HCV is associated with membranoproliferative glomerulonephritis, acceleration of end-stage renal diseases in patients with glomerulopathies, and a higher risk of death in patients affected by chronic kidney disease. Before the introduction of direct-acting antiviral drugs as treatment modality, renal transplantation was a challenging clinical problem because the drugs available until 2011 obtained a poor sustained virologic response, had several side effects, and caused acute rejection when used after transplantation. The knowledge of the viral structure and its replication allowed the discovery of new classes of direct-acting antiviral drugs that revolutionized this scenario. These new drugs are comparatively more effective and safer. Accumulating evidence suggests that it is possible to cure HCV-related glomerulonephritis, and obtain a sustained virologic response in patients with renal failure, or on dialysis, before commencing transplantation. Finally, it became possible to transplant HCV-positive kidneys into HCV-positive or HCV-negative recipients.

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