The role of treatment of hepatitis C with direct-acting antiviral agents on glycaemic control in diabetic patients: An updated systematic review and meta-analysis.

Recent studies suggested that successful clearance of chronic Hepatitis C Virus (HCV) by using direct-acting antiviral (DAA) agents could improve glycemic control in patients with diabetes; however, some studies failed to identify this benefit. We conducted a systematic review and meta-analysis to assess the impact of sustained virologic response (SVR) after treatment with DAA agents on glycemic control. Embase, Scopus and PubMed were searched through March 26th, 2023, for all studies evaluating whether eradication of HCV infection with DAAs is associated with an impact on glycemic control. Only studies with data on glycemic control, including haemoglobin A1c (HbA1c), fasting glucose, or Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), at least 12-week post-SVR were included. Sixteen studies met our eligibility criteria and were included in qualitative analysis. The mean HbA1c was 8.05% (95% CI: 7.79%-8.31%) before treatment and 7.19% (95% CI: 6.98%-7.39%) after treatment. There was a significant mean absolute reduction in HbA1c of 0.72% (95% CI: 0.52%-0.93%) with high heterogeneity between studies (I2 = 91.7%). The reduction in HbA1c remained significant in the subgroup analysis at 3 months follow up post SVR [0.74% (95% CI: 0.57%-0.91%)] and at least 6 months follow up [0.66% (95% CI: 0.23%-1.10%)]. We found a significant reduction in HbA1C after SVR in patients with type 2 diabetes mellitus, reflecting better glycemic control with HCV eradication. This data highlights an important extrahepatic benefit of HCV eradication.

Exploring current and emerging therapies for porphyrias.

Porphyrias are rare, mostly inherited disorders resulting from altered activity of specific enzymes in the haem synthesis pathway that lead to accumulation of pathway intermediates. Photocutaneous symptoms occur when excess amounts of photoreactive porphyrins circulate in the blood to the skin, whereas increases in potentially neurotoxic porphyrin precursors are associated with neurovisceral symptoms. Current therapies are suboptimal and their mechanisms are not well established. As described here, emerging therapies address underlying disease mechanisms by introducing a gene, RNA or other specific molecule with the potential to cure or slow progression of the disease. Recent progress in nanotechnology and nanoscience, particularly regarding particle design and formulation, is expanding disease targets. More secure and efficient drug delivery systems have extended our toolbox for transferring specific molecules, especially into hepatocytes, and led to proof-of-concept studies in animal models. Repurposing existing drugs as molecular chaperones or haem synthesis inhibitors is also promising. This review summarizes key examples of these emerging therapeutic approaches and their application for hepatic and erythropoietic porphyrias.

Real-world experience in treatment of donor-derived Hepatitis C virus in kidney transplant recipients with delayed initiation, shortened course glecaprevir/pibrentasvir versus standard of care.

BACKGROUND: There is limited literature describing the real-world practice of delayed initiation and shortened duration direct-acting antiviral (DAA) in kidney transplant recipients. We compared Hepatitis C virus (HCV) cure rates among kidney transplant recipients who received an HCV nucleic acid test positive (NAT +) kidney and were treated with sofosbuvir/velpatasvir (SOF/VEL) for 12 weeks or glecaprevir/pibrentasvir (G/P) for 8 weeks, a duration that is 4 weeks shorter than the guideline recommendation for treatment delay beyond 1-week post-transplant. METHODS: Retrospective study of HCV-negative adult patients who received a kidney transplant from an HCV NAT+ donor between April 2019 and April 2022 treated with either SOF/VEL for 12 weeks or G/P for 8 weeks. The primary outcome was sustained virologic response 12 weeks after completion of therapy (SVR12). Secondary outcomes included time to DAA initiation, renal function, graft loss, patient death, liver function tests, and opportunistic infections. RESULTS: 102 kidney transplant recipients were included with 36 treated with G/P and 66 treated with SOF/VEL. All 36 (100%) treated with G/P achieved SVR12. One patient in the SOF/VEL group failed to achieve SVR12 but received additional therapy and was cured. Time to DAA initiation was similar with a mean of 4 weeks. There was no difference in AST/ALT > 3x ULN or renal function. One rejection occurred in each group. No patient death or graft loss was observed. There was no difference in cytomegalovirus and BK viremia between groups.  CONCLUSION: Delayed initiation of DAA therapy with 12 weeks of SOF/VEL or 8 weeks of G/P achieves SVR12 in kidney transplant recipients without significant adverse effects.

Metabolic management after sustained virologic response in elderly patients with hepatitis C virus: A multicenter study.

AIMS: Hepatocellular carcinoma (HCC) develops even in patients with hepatitis C virus (HCV) eradication by direct-acting antiviral agents. Fatty liver and metabolic dysfunction are becoming major etiologies of HCC. We aimed to evaluate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD), a new definition of steatotic liver disease, on the development of HCC after HCV eradication. METHODS: We enrolled 1280 elderly patients with HCV eradication and no history of HCC. We evaluated α-fetoprotein (AFP), Fibrosis-4 index and MASLD after 24 weeks of sustained virological response. Decision tree analysis was used to investigate factors associated with HCC development after HCV eradication. RESULTS: A total of 86 patients (6.7%) developed HCC during the follow-up period (35.8 ± 23.7 months). On multivariate analysis, serum AFP level (HR 1.08, CI 1.04-1.11, P = 0.0008), Fibrosis-4 index (HR 1.17, CI 1.08-1.26, P = 0.0007), and MASLD (HR 3.04, CI 1.40-6.58, P = 0.0125) at 24 weeks of sustained virological response were independent factors associated with HCC development. In decision tree analysis, the initial classifier for HCC development was AFP ≥7 ng/mL. However, in patients with AFP <7 ng/mL, MASLD, rather than Fibrosis-4 index, was the classifier for HCC development. No significant difference was observed in the cumulative incidence of HCC between patients with AFP ≥7 ng/mL and patients with AFP <7 ng/mL and MASLD. CONCLUSION: MASLD at 24 weeks of sustained virological response is a risk factor for HCC development in elderly patients with HCV eradication. Additionally, decision tree analysis revealed that MASLD was associated with HCC development, even in patients with serum AFP levels <7 ng/mL.

Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

BACKGROUND: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. METHODS: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. RESULTS: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). CONCLUSION: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

Effects of sustained viral response on lipid in Hepatitis C: a systematic review and meta-analysis.

BACKGROUND: Direct-acting Antiviral Agents (DAAs) influence serum lipids of patients with Hepatitis C virus (HCV). This paper presents an analysis of the relevant literature to investigate the effects of DAAs in treating hepatitis C to achieve a sustained viral response (SVR) on lipid parameters. METHODS: PubMed,Web of science, Embase and Central databases were searched, with a deadline of September 2023. Studies on the effects of sustained viral response on lipid parameters after DAAs treatment for hepatitis C were selected. The required information was extracted from the included studies, and then the Stata 12.0 was used to analyze the data quantitatively. RESULTS: Of 32 studies, the results showed that total cholesterol (TC) levels increased from the end of treatment (WMD = 20.144, 95%CI = 3.404, 36.884,P = 0.018) to one year after treatment (WMD = 24.900, 95%CI = 13.669, 36.131, P < 0.001). From the end of treatment (WMD = 17.728, 95%CI = 4.375, 31.082, P = 0.009) to one year after treatment (WMD = 18.528, 95%CI = 7.622, 29.433, P < 0.001), the levels of low-density lipoprotein (LDL) were also increased. High-density lipoprotein (HDL) levels were elevated from 4 weeks after treatment (WMD = 6.665, 95%CI = 3.906, 9.424, P < 0.001) to 24 weeks after treatment (WMD = 3.159,95% CI = 0.176, 6.142, P = 0.038). Triglyceride (TG) levels showed no significant change after the treatment. CONCLUSIONS: Hepatitis C patients who achieved SVR on DAAs showed the increase of lipid levels and the improvement of hepatic inflammation indicators AST and ALT. This may provide evidence-based medical evidence for the follow-up and monitoring of blood lipids and hyperlipidemia treatment. REGISTRATION: PROSPERO CRD42020180793.

Surveillance and management of hepatocellular carcinoma after treatment of hepatitis C with direct-acting antiviral drugs.

Hepatitis C virus (HCV) belongs to the Flaviviridae family, and is a single-stranded RNA virus with positive polarity. It is the primary cause of hepatocellular carcinoma (HCC) worldwide. The treatment of HCV has entered a new era with the advent of direct-acting antiviral drugs (DAAs) and is associated with cure rates of more than 95 %, making HCV the only curable viral disease. The successful treatment of chronic hepatitis C has greatly reduced, but not eliminated, the risk of HCC. Certain individuals, especially those with cirrhosis already present, remain vulnerable to HCC after achieving a sustained virological response (SVR). This article systematically reviews the recent studies on the risk and mechanisms of HCC development after HCV viral cure, the screening and predictive value of biological markers, and patient surveillance. Factors such as older age, diabetes, hepatic fat accumulation, alcohol use, and lack of fibrosis reversal are linked to increased HCC risk after HCV cure. The mechanism of HCC development after DAAs treatment remains unclear, but the possible mechanisms include immune cell dysfunction during HCV infection, cytokine network imbalance, epigenetic alterations, and host factors. Several biological markers and risk prediction models have been used to monitor the risk of HCC in CHC patients who have achieved SVR, but most still require validation and standardization. The implementation of risk-stratified surveillance programs is becoming urgent from a cost-effective point of view, but the availability of validated biomarkers to predict HCC in cured patients remains an unmet clinical need. Additionally, managing CHC patients who achieve SVR is becoming a growing challenge as an increasing number of HCV patients are cured.

Prospective Assessment of Serum Lipid Alterations in Chronic Hepatitis C Patients Treated with Direct Acting Antivirals: Insights Six Months Post Sustained Virological Response.

Background and Objectives: Chronic hepatitis C virus (HCV) infection is intricately linked with dysregulation of lipid metabolism. In particular, cholesterol plays a crucial role in HCV replication. Direct-acting antiviral agents (DAAs) therapy has revolutionized the hepatitis C treatment landscape, achieving high rates of sustained virological response (SVR). However, viral clearance comes with some alterations in lipid-related markers. This prospective study aimed to evaluate the impact of HCV clearance on lipid homeostasis and non-invasive liver fibrosis markers in hepatitis C patients treated with DAAs. Material and Methods: Fifty-two patients with varying degrees of fibrosis treated with DAAs therapy were evaluated at baseline and 24 weeks post-SVR. Lipid profiles and non-invasive liver fibrosis markers were assessed. Results: Our findings revealed an increase in total cholesterol, triglyceride, and LDLc (low-density lipoprotein cholesterol) levels at 24 weeks post-SVR, alongside an improvement in serum liver enzymes. Although improvements in liver stiffness were observed in non-invasive tests, there was an increase in lipid-related markers post-SVR. Conclusions: This suggests a potential increased cardiovascular risk despite improvements in liver function and fibrosis, highlighting the necessity for statin therapy in some cases and extended follow-ups for these patients. These findings underscore the importance of closely monitoring lipid profiles in chronic hepatitis C patients post-SVR, as well as the potential need for statin therapy to mitigate cardiovascular risk. Additionally, extended follow-up is essential to assess long-term outcomes and ensure the optimal management of these patients.

[Research progress of direct-acting antiviral drugs in the treatment of chronic hepatitis C-related cirrhosis].

Chronic hepatitis C is a kind of viral hepatitis caused by hepatitis C virus infection, which can further progress to cirrhosis, liver failure, hepatocellular carcinoma, and even death. Presently, there is no preventive vaccine yet. Therefore, preventing infection and safe and effective drug treatment are currently the most effective strategies for dealing with hepatitis C virus infection. Since 2014, the clinical application of direct-acting antiviral drugs has brought revolutionary changes to the treatment of chronic hepatitis C. Direct-acting antiviral drugs have an excellent hepatitis C virus clearance effect, are well tolerated, have a good safety profile, and can significantly improve liver function, metabolic disorders, immune dysfunction, etc. However, some studies have pointed out that even if the hepatitis C virus is cleared during the treatment of chronic hepatitis C-related cirrhosis with direct-acting antiviral drugs, a considerable proportion of patients still have severe liver failure, hepatocellular carcinoma, and even liver disease-related death, so there are still some problems in the treatment of chronic hepatitis C- related cirrhosis with direct-acting antiviral drugs that need to be further explored. This article reviews the research progress of direct-acting antiviral drugs so as to provide meaningful references for the treatment of patients with chronic hepatitis C-related cirrhosis.

Targeting ER stress/PKA/GSK-3ß/ß-catenin pathway as a potential novel strategy for hepatitis C virus-infected patients.

BACKGROUND: Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). The HCC risk, while decreased compared with active HCV infection, persists in HCV-cured patients by direct-acting antiviral agents (DAA). We previously demonstrated that Wnt/ß-catenin signaling remained activated after DAA-mediated HCV eradication. Developing therapeutic strategies to both eradicate HCV and reverse Wnt/ß-catenin signaling is needed. METHODS: Cell-based HCV long term infection was established. Chronically HCV infected cells were treated with DAA, protein kinase A (PKA) inhibitor H89 and endoplasmic reticulum (ER) stress inhibitor tauroursodeoxycholic acid (TUDCA). Western blotting analysis and fluorescence microscopy were performed to determine HCV levels and component levels involved in ER stress/PKA/glycogen synthase kinase-3ß (GSK-3ß)/ß-catenin pathway. Meanwhile, the effects of H89 and TUDCA were determined on HCV infection. RESULTS: Both chronic HCV infection and replicon-induced Wnt/ß-catenin signaling remained activated after HCV and replicon eradication by DAA. HCV infection activated PKA activity and PKA/GSK-3ß-mediated Wnt/ß-catenin signaling. Inhibition of PKA with H89 both repressed HCV and replicon replication and reversed PKA/GSK-3ß-mediated Wnt/ß-catenin signaling in both chronic HCV infection and replicon. Both chronic HCV infection and replicon induced ER stress. Inhibition of ER stress with TUDCA both repressed HCV and replicon replication and reversed ER stress/PKA/GSK-3ß-dependent Wnt/ß-catenin signaling. Inhibition of either PKA or ER stress both inhibited extracellular HCV infection. CONCLUSION: Targeting ER stress/PKA/GSK-3ß-dependent Wnt/ß-catenin signaling with PKA inhibitor could be a novel therapeutic strategy for HCV-infected patients to overcomes the issue of remaining activated Wnt/ß-catenin signaling by DAA treatment. Video Abstract.

High real-world effectiveness of 12-week elbasvir/grazoprevir without resistance testing in the treatment of patients with HCV genotype 1a infection in Norway.

BACKGROUND AND AIMS: The recommended treatment duration of hepatitis C virus (HCV) genotype 1a (GT1a) infection with elbasvir/grazoprevir (EBR/GZR) in the presence of a high baseline viral load and resistance associated substitutions (RAS) is 16 weeks with ribavirin added. The objective of this study was to evaluate the real-world effectiveness of 12 weeks of EBR/GZR without ribavirin and regardless of baseline viral load and RAS testing. METHOD: This retrospective, observational cohort study was performed at five Norwegian hospitals that did not systematically utilize RAS testing. All adult patients with chronic HCV GT1a and compensated liver disease who had received 12 weeks of EBR/GZR without ribavirin and baseline RAS testing, were included. The primary endpoint was sustained virologic response at week 12 (SVR12), or if not available, at week 4 (SVR4). RESULTS: We included 433 patients and attained SVR data on 388. The mean age was 45.7 years (22-73 years). 67.2% were male. HIV co-infection was present in 3.8% (16/424) and cirrhosis in 4% (17/424). The viral load was >800 000 IU/mL in 55.0% (235/427) of patients. Overall SVR was achieved in 97.2% (377/388). SVR was achieved in 98.3% (169/172) of those with viral load ≤800 000 IU/mL and in 96.2% (202/210) of those with viral load >800 000 IU/mL. CONCLUSION: We observed high SVR rates among patients with HCV GT1a infection treated with EBR/GZR for 12 weeks without ribavirin, with no regard to baseline viral load and no RAS testing.

Regression in hepatic fibrosis in elderly Chinese patients with hepatitis C receiving direct-acting antiviral treatment.

BACKGROUND: Patients infected with Hepatitis C virus (HCV) are recommended to receive treatment with direct-acting antiviral agents (DAAs), which have been certified to obtain a high sustained virological response (SVR). However, little is known about the benefits of successful anti-viral treatment to elderly patients with hepatic fibrosis. In this study, we aimed to assess degree of fibrosis in elderly patients with chronic hepatitis C (CHC) treated with DAAs, and to evaluate the correlations between identified factors associated with these changes. METHODS: This study retrospectively enrolled elderly patients with CHC who received DAAs in Tianjin Second People's Hospital from April 2018 to April 2021. The degree of liver fibrosis was assessed using serum biomarkers and transient elastography (TE) expressed as the liver stiffness (LSM), while the hepatic steatosis was evaluated by controlled attenuated parameter (CAP). Changes in factors related to hepatic fibrosis were examined following treatment with DAAs, and associated prognostic factors were further evaluated. RESULTS: We included 347 CHC patients in our analysis, where 127 of these were elderly patients. For the elderly group, the median LSM was 11.6 (7.9-19.9) kPa, and this value was significantly reduced to 9.7 (6.2-16.6) kPa following DAA treatment. Similarly, GPR, FIB-4 and APRI indices were significantly reduced from 0.445 (0.275-1.022), 3.072 (2.047-5.129) and 0.833 (0.430-1.540) to 0.231 (0.155-0.412), 2.100 (1.540-3.034) and 0.336 (0.235-0.528), respectively. While in younger patients, the median LSM reduced from 8.8 (6.1-16.8) kPa to 7.2 (5.3-12.4) kPa, and the trends of GPR, FIB-4 and APRI were also consistent. The CAP in younger patients increased with statistical significance, but we did not observe any significant change in CAP for the elderly group. Based on multivariate analysis, age, LSM, and CAP before baseline were identified as determinants for LSM improvement in the elderly. CONCLUSION: In this study, we found that elderly CHC patients treated with DAA had significantly lower LSM, GPR, FIB-4, and APRI values. DAA treatment did not significantly change CAP. Furthermore, we observed correlations between three noninvasive serological evaluation markers and LSM. Finally, age, LSM, and CAP were identified as independent predictors of fibrosis regression in elderly patients with CHC.

Introduction of direct-acting antiviral agents alters frequencies of anti-GPIIb/IIIa antibody-producing B cells in chronic hepatitis C patients with thrombocytopenia.

The pathogenesis of thrombocytopenia in chronic hepatitis C (CHC) conceivably involves autoimmunity; however, the dynamics of autoantibodies and other autoimmune mechanisms remain unclear. In this study, we examined the changes in the frequency of anti-glycoprotein (GP) IIb/IIIa antibody-producing B cells and the levels of plasma B-cell-activating factor (BAFF), a proliferation-inducing ligand (APRIL), and interleukin (IL)-21 following treatment of CHC with direct-acting antiviral agents (DAA). We recruited 28 patients with CHC who underwent treatment with DAA for 8-12 weeks and subsequently tested negative for serum hepatitis C virus RNA. Thirty healthy controls were recruited for comparison. Platelet counts increased significantly (p = .016), and the frequency of anti-GPIIb/IIIa antibody-producing B cells decreased significantly (p = .002) in CHC patients with thrombocytopenia at the end of treatment (EOT) than before DAA treatment (baseline). However, these changes were not observed in CHC patients without thrombocytopenia. Plasma BAFF levels in CHC patients with thrombocytopenia significantly decreased from baseline to EOT (p = .002). Anti-GPIIb/IIIa antibody-producing B cells were positively correlated with plasma BAFF levels in these patients (r = 0.669, p = .039). These results suggest that DAA treatment suppresses the autoimmune response against platelets and improves thrombocytopenia.

What is the context? Production of antiplatelet antibodies is one of the mechanisms underlying thrombocytopenia in patients with chronic hepatitis C.Antiplatelet antibodies against platelet membrane glycoprotein (GP) IIb/IIIa are commonly detected in hepatitis C virus-associated immune thrombocytopenia.Hepatitis C virus elimination by direct-acting antiviral agents (DAA) improves thrombocytopenia in patients with hepatitis C; however, the dynamics of autoantibodies and other autoimmune mechanisms remain unclear.What is new? In this study, we determined whether DAA treatment can alter the autoimmune response against platelets and improve platelet count.The frequency of anti-GPIIb/IIIa antibody-producing B cells decreased significantly from the baseline following DAA treatment in chronic hepatitis C patients with thrombocytopenia.DAA treatment reduced the levels of B-cell-activating factor, a cytokine associated with autoantibody production.What is the impact? The study provides evidence that DAA treatment diminishes the autoimmune response to GPIIb/IIIa and, therefore, improves platelet counts in chronic hepatitis C patients with thrombocytopenia.

Usefulness Of Sofosbuvir And Daclatasvir Combination In The Treatment Of HCV Infection In Childhood Cancer Patients: Experience From A Tertiary Care Hospital.

Objectives: To determine the usefulness of Sofosbuvir-Daclatasvir combination in the treatment of hepatitis c virus infection in paediatric cancer.. METHODS: The retrospective study was conducted at the Oncology Department of the National Institute of Child Health, Karachi, and comprised medical charts of patients who received sofosbuvir and daclatasvir from January 2018 to January 2022. Efficacy was documented by clearance of hepatitis C virus ribonucleic acid as rapid viral response, early viral response and sustained viral response at weeks 4, 12 and 24, respectively. Drug efficacy was determined by monitoring and recording adverse effects. Chemotherapy protocol for the treatment of patients concomitantly receiving direct acting antivirals was modified while looking at drug-drug interactions. The total duration of direct acting antiviral therapy was 12 weeks. Data was analysed using SPSS 24. RESULTS: Of the 804 patients with different malignancies, 132(16.4%) were found positive for hepatitis C virus. Of them, 28(21.21%) patients were started on direct acting antivirals; 17(60.71%) boys and 11(39.28%) girls. The overall mean age was 9.93±6.12 years. The diagnosis was pre-B acute lymphoblastic leukaemia in 18(64.28%) cases, 16 (57.14%) were on maintenance chemotherapy, and 18(64.28%) had genotype 1. Pre- and post-treatment mean alanine transaminase levels were 328.00±324.00IU and 36.00±29.00IU, respectively (p=0.003). Pre- and post- treatment mean serum bilirubin levels were 3.13±3.95mg/dl and 0.61±0.21mg/dl (p=0.022). Rapid viral response was achieved in 26(92.85%) children, while early viral response and sustained viral response were achieved in all 28(100%) patients. Minor side effects were noted in 4(14.28%) patients and chemotherapy was continued in all 28(100%) cases as per the designed protocol. CONCLUSIONS: The sofosbuvir-daclatasvir combination was found to be effective in hepatitis C virus treatment in paediatric cancer patients.

Hypoglycemia associated with direct-acting anti-hepatitis C virus drugs: An epidemiologic surveillance study of the FDA adverse event reporting system (FAERS).

BACKGROUND AND OBJECTIVE: Hypoglycemia induced by direct-acting antiviral agents (DAAs) for chronic hepatitis C virus (HCV) infection is a rare but potentially life-threatening adverse reaction, which led to warnings by competent authorities. We therefore aimed to examine the hypoglycemic safety signal for DAAs. METHODS: Reports to the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 1 October 2012 to 31 March 2020 were analyzed. The Medical Dictionary for Regulatory Activities was used to identify hypoglycemia cases. A case by non-case disproportionality approach was used whereby reporting odds ratio (ROR) with 95% confidence intervals (CI) were calculated. RESULTS: In HCV infection with diabetes patients, the cumulative frequency of hypoglycemic ADRs was 21.85/1000 for reports involving DAAs versus 13.50/1000 for reports involving other medications; For DAAs as a class drug, a nearly double increased reporting odds for hypoglycemia was observed (ROR: 1.63, 95% CI: 1.11-2.41). However, in DAAs subgroup analysis, only telaprevir (ROR: 1.66, 95% CI: 1.01-2.74) and elbasvir/grazoprevir (ROR: 2.25, 95% CI: 1.05-4.83) were associated with increased reporting risk of hypoglycemia during corresponding marketing period; when combined with insulins and sulfonylureas, DAAs were associated with increased reporting risk for hypoglycemia (ROR: 1.98, 95% CI: 1.36-2.88; ROR: 1.62, 95% CI: 1.06-2.48), but concomitant biguanides, dipeptidyl peptidase IV (DPP-4) inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1RAs) were not significant. CONCLUSIONS: This study supports the current recommendation for cautious about hypoglycemic risk relating to the use of DAAs. Treatment with DAAs and antidabetic agents (especially insulins and sulfonylureas) will increase hypoglycemia reporting risk. Physicians and pharmacists should be aware of this risk when prescribing DAAs for patients suffering from diabetes, advanced age or liver decompensation.

Prevalence and risk factors for hepatocellular carcinoma in individuals with haemophilia in the era of direct-acting antiviral agents: A national inpatient sample study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a major complication of chronic hepatitis C virus (HCV) infection. Among haemophilic (H) men, HCV is the leading cause of liver disease. Direct-acting antiviral agents (DAA) reduce HCV viral load, but impact on HCC is unknown. METHODS: This was a retrospective study of adult H and nonhaemophilic (NH) male discharges, with and without HCC, identified by ICD-10 codes in the National Inpatient Sample (NIS) database, 2016-2018, with DAA availability. Analyses included discharge-level weights to reflect national estimates. Categorical variables were assessed by Rao-Scott chi-square and continuous variables by weighted simple linear regression. HCC correlates were determined by weighted multivariable logistic regression. RESULTS: Among 7,674,969 adult male discharges, 3730 H (.04%) were identified in 2016-2018, of whom 10.06% had HCV and 1.07% had HCC, significantly higher than NH (1.22% and .27%, respectively) all P < .001. Annual HCC rates were similar during the 3-year period (2016-2018) in H and NH. Among H, HCC is associated with older age and higher rates of HCV, HBV, NASH, end-stage liver disease, and Charlson comorbidity (CCI), each P < .001. Among HCC, H were younger and more likely HIV+, each P < .001, but less likely alcoholic (P = .018) or hyperlipidaemic (P = .008) compared to NH. In multivariable regression, risk factors for HCC among H included NASH (OR 21.6), HCV (OR 3.96), CCI (OR1.54), all P < .001, while HIV and hyperlipidaemia were protective. CONCLUSION: From 2016 to 2018, HCC rates did not change significantly in haemophilia discharges. NASH, HCV, and CCI are significant risks for HCC in haemophilia during the DAA-era.

Effects of direct-acting antiviral treatment on reducing mortality among Medicare beneficiaries with HIV and HCV coinfection.

Hepatitis C virus (HCV) infection is common among people living with HIV. HIV and HCV coinfected patients have higher overall mortality rates compared with HIV mono-infected patients. With its high cure rate of HCV infection, direct-acting antiviral (DAA) treatment provides an opportunity to improve the survival of the HIV/HCV coinfected population. The objective of this study is to investigate the association between DAA treatment and all-cause mortality among HIV/HCV coinfected people. The study included 7103 Medicare beneficiaries in the United States who were infected with both HIV and HCV between 2014 and 2017. Cox proportional hazards regression model was used to estimate adjusted hazard ratios (aHRs) of death for patients with and without DAA treatment while controlling for patient characteristics. During the study period, 1675 patients initiated DAA treatment (23.6%). The adjusted hazard ratio (aHR) of all-cause mortality between patients with and without DAA treatment was 0.37 (95% CI, 0.29-0.48), regardless of cirrhosis status. DAA treatment was associated with a smaller reduction in all-cause mortality for females (aHR, 0.50 [95% CI, 0.30-0.85]) compared with males (aHR, 0.34 [95% CI, 0.25-0.46]). DAA treatment was associated with improved survival among all HIV/HCV coinfected patients regardless of sex or HCV disease progression.

Interferon at the cellular, individual, and population level in hepatitis C virus infection: Its role in the interferon-free treatment era.

The advent of powerful direct-acting antiviral agents (DAAs) has revolutionized the treatment of hepatitis C. DAAs cure nearly all patients with short duration, oral treatments. Significant efforts are now underway to optimize DAA-based treatments. We discuss the potential role of interferon in this optimization. Clinical studies present compelling evidence that DAAs perform better in treatment-naive individuals than in individuals who previously failed treatment with interferon, a surprising correlation because interferon and DAAs are thought to act independently. Recent mathematical models explore a mechanistic hypothesis underlying this correlation. The hypothesis invokes the action of interferon at the cellular, individual, and population levels. Strong interferon responses prevent the productive infection of cells, reduce viral replication, and impede the development of resistance to DAAs in infected individuals and improve cure rates elicited by DAAs in treated populations. The models develop descriptions of these processes, integrate them into a comprehensive framework, and capture clinical data quantitatively, providing a successful test of the hypothesis. Individuals with strong endogenous interferon responses thus present a promising subpopulation for reducing DAA treatment durations. This review discusses the conceptual advances made by the models, highlights the new insights they unravel, and examines their applicability to optimize DAA-based treatments.

Comparison of the Efficacies of Direct-Acting Antiviral Treatment for HCV Infection in People Who Inject Drugs and Non-Drug Users.

Background and Objectives: Hepatitis C virus (HCV) is a major cause of liver disease worldwide. People who inject drugs (PWIDs) constitute the majority of patients with HCV infection in the United States and Central Asia. There are several obstacles to treating HCV infection in PWIDs because PWIDs are often accompanied by concurrent infection, low compliance, substance abuse, and risky behavior. The aim of the study is to compare the efficacies of direct-acting antiviral (DAA) therapy for HCV infection in PWIDs and those without opioid injection. Materials and Methods: In this retrospective cohort study, we included 53 PWIDs with HCV infections treated on site in a methadone program and 106 age- and sex-matched patients with HCV infections who had no history of opioid injection (ratio of 1:2). All eligible subjects received anti-HCV treatment by DAA agents in our hospital from March 2018 to December 2020. The charts of these patients were carefully reviewed for demographic data, types of DAA agents, and treatment outcomes. The primary outcome measure was sustained virological response (SVR). Results: PWIDs and non-drug users had different HCV genotype profiles (p = 0.013). The former had higher proportions of genotype 3 (18.9% vs. 7.5%) and genotype 6 (24.5% vs. 14.2%) than the latter. The two patient groups had comparable rates of complete drug refilling (100.0% vs. 91.1%) and frequency of loss to follow-up (3.8% vs. 0.9%). However, PWIDs had a lower SVR rate of DAA treatment than non-drug users (92.2% vs. 99.0%; p = 0.04). Further analysis showed that both human immunodeficiency virus (HIV) coinfection and history of PWID were risk factors associated with treatment failure. The subjects with coinfection with HIV had lower SVR rates than those without HIV infection (50.0% vs. 96.5%; p = 0.021). Conclusions: PWIDs with HCV infections have higher proportions of HCV genotype 3 and genotype 6 than non-drug users with infections. DAA therapy can achieve a high cure rate (>90%) for HCV infection in PWID, but its efficacy in PWID is lower than that in non-drug users.

[Treatment of parenterally transmittable viral hepatitis]. / Therapie der parenteral übertragbaren Virushepatitiden.

The parenterally transmittable hepatitides B, D and C and their complications are a problem worldwide and also in Germany that should not be underestimated. Due to the estimated high gray area, a broad distribution, particularly by drug abuse, increasing prevalence due to immigration and a pandemic-related delay in the diagnostics, the identification of affected persons and therefore potentially infectious patients represents a great challenge for the healthcare system. Highly effective treatment concepts with practically no side effects and a tablet ingestion once daily are available for hepatitis B and also hepatitis C. For hepatitis B this involves long-term treatment for suppression of replication, whereas for hepatitis C virus elimination occurs within a few weeks. A new treatment concept with inhibition of virus uptake for treatment of hepatitis D first became available in September 2020. For all patients a long-term further monitoring is necessary when advanced liver damage or even liver cirrhosis occurs, especially for the exclusion of liver cell carcinoma.