Use Of Direct-acting Antivirals Research Articles

Hepatitis C Virus Infection in Europe.

The Hepatitis C Virus (HCV) is a significant public health challenge in European countries. Historically, healthcare-related procedures were the primary source of HCV infection in Europe. However, with the implementation of blood safety programs, injection drug use has become the main transmission route. The infection's distribution and genotype prevalence vary widely across the continent. Even with the availability of highly effective direct-acting antiviral (DAA) therapies, HCV infection is far from being controlled. A significant proportion of patients remain undiagnosed, contributing to the ongoing transmission of the virus. Additionally, several barriers hinder the widespread use of DAAs, including high treatment costs, stigma, poor linkage to care, and considerable geographical variations in prevalence and transmission routes. The World Health Organization has set ambitious targets to reduce liver-related deaths, decrease new viral hepatitis infections, and ensure that 90% of infected individuals are diagnosed by 2030. However, most European countries face challenges, highlighting the need for screening programs, funding mechanisms, and public health strategies to effectively control HCV infection in Europe.

Efficacy of late-onset antiviral treatment in immunocompromised hosts with persistent SARS-CoV-2 infection.

Four years after the onset of the global coronavirus disease 2019 (COVID-19) pandemic, the immunocompromised are at greatest risk of developing life-threatening severe disease. However, specific treatment plans for this most vulnerable patient group have not yet been developed. Employing a CD4+ and CD8+ T cell-depleted immunocompromised mouse model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we explored therapeutic options of persistent infections with standard-of-care paxlovid, molnupiravir, and the experimental therapeutic 4'-fluorouridine (4'-FlU). Late-onset treatment initiated 14 days after infection was efficacious, but only 4'-FlU was rapidly sterilizing. No treatment-experienced viral variants with reduced susceptibility to the drugs emerged, albeit virus replication rebounded in animals of the paxlovid group after treatment end. This study supports the use of direct-acting antivirals (DAAs) for late-onset management of persistent SARS-CoV-2 infection in immunocompromised hosts. However, treatment courses likely require to be extended for maximal therapeutic benefit, calling for appropriately powered clinical trials to meet the specific needs of this patient group.

Overview of Hepatitis C in Pregnancy: Screening, Management and Treatment.

The rising prevalence of hepatitis C infections among individuals of reproductive age further emphasizes the importance of evidence-based management of HCV during pregnancy to minimize perinatal transmission and to optimize maternal and fetal outcomes. In this review, we discuss the most recent recommendations on the management of HCV in pregnancy, including recommendations for screening and treatment during pregnancy and the postpartum period, as well as infant management to reduce perinatal transmission of HCV. Current guidelines recommend universal HCV screening during each pregnancy. With varying guidance regarding the use of direct-acting antivirals (DAAs) during pregnancy, recent studies have focused on the safety and efficacy of DAA initiation during pregnancy. Additionally, there has been an increased focus on improving treatment rates in the postpartum period through innovative linkage to care efforts, telemedicine, and additional efforts reducing barriers to care for patients.

Effect of Direct Acting Antiviral Drugs on the Occurrence and Recurrence of Intra- and Extra-Hepatic Malignancies in Patients with Chronic Hepatitis C Virus Infection.

Introduction: The use of direct-acting antivirals (DAAs) has drastically changed the management of HCV-infected patients by achieving a 95-98% sustained virologic response (SVR) and reducing morbidity and mortality in this population. However, despite their effectiveness, controversy exists concerning the occurrence of oncologic events following DAA therapy. Aims and Methods: A retrospective analysis was conducted on data from the Swiss Hepatitis C Cohort Study, a prospective cohort involving patients with positive HCV viremia upon inclusion, enrolled in various Swiss centers from September 2000 to November 2021. To examine potential differences in the risk of intrahepatic tumor (IHT) occurrence and death among patients treated with direct-acting antivirals (DAAs), untreated patients, and those receiving interferon (IFN)-based therapy, a semiparametric competing risk proportional hazards regression model was used. Results: Among 4082 patients (63.1% male, median age 45 years; genotype 1: 54.1%; cirrhosis: 16.1%), 1026 received exclusive treatment with IFN-based regimens, and 1180 were treated solely with DAAs. Over a median follow-up of 7.8 years (range: 3.8-11.9), 179 patients (4.4%) developed intrahepatic tumors (IHT), and 168 (4.1%) experienced extrahepatic tumors (EHT). The 5-year cumulative incidence of IHT was 1.55% (95% CI 0.96-2.48) for IFN-based therapy, 4.27% (95% CI 2.93-6.2) for DAA and 0.89% (95% CI 0.4-1.99) for untreated patients. There was no statistically significant difference in the risk of developing IHT (HR = 1.34; 95% CI = [0.70; 2.58]; p = 0.380) or death (HR = 0.66; 95% CI = [0.43; 1.03]; p = 0.066) between patients treated with DAAs and those treated with IFN. Conclusions: The DAAs reduced the risk of death and were not associated with an increased risk of extrahepatic tumors (EHT). In the adjusted model, accounting for cirrhosis and high liver stiffness, the DAA treatment was associated with a higher risk of IHT occurrence compared with untreated patients, emphasizing the relevance of implementing standardized hepatocellular carcinoma (HCC) screening post-DAA treatment.

Changes in Use of Hepatitis C Direct-Acting Antivirals After Access Restrictions Were Eased by State Medicaid Programs

Direct-acting antivirals (DAAs) are safe and highly effective for curing hepatitis C virus (HCV) infection, but their high cost led certain state Medicaid programs to impose coverage restrictions. Since 2015, many of these restrictions have been lifted voluntarily in response to advocacy or because of litigation. To estimate how the prescribing of DAAs to Medicaid patients changed after states eased access restrictions. This modified difference-in-differences analysis of 39 state Medicaid programs included Medicaid beneficiaries who were prescribed a DAA from January 1, 2015, to December 31, 2019. DAA coverage restrictions were measured based on a series of cross-sectional assessments performed from 2014 through 2022 by the US National Viral Hepatitis Roundtable and the Center for Health Law and Policy Innovation. Calendar quarter when states eased or eliminated 3 types of DAA coverage restrictions: limiting treatment to patients with severe liver disease, restricting use among patients with active substance use, and requiring prescriptions to be written by or in consultation with specialists. States with none of these restrictions at baseline were excluded. Quarterly number of HCV DAA treatment courses per 100 000 Medicaid beneficiaries. Of 39 states, 7 (18%) eliminated coverage restrictions, 25 (64%) eased restrictions, and 7 (18%) maintained the same restrictions from 2015 to 2019. During this period, the average quarterly use of DAAs increased from 669 to 3601 treatment courses per 100 000 Medicaid beneficiaries. After states eased or eliminated restrictions, the use of DAAs increased by 966 (95% CI, 409-1523) treatment courses per 100 000 Medicaid beneficiaries each quarter compared with states that did not ease or eliminate restrictions. The results of this study suggest that there was greater use of DAAs after states relaxed coverage restrictions related to liver disease severity, sobriety, or prescriber specialty. Further reductions or elimination of these rules may improve access to a highly effective public health intervention for patients with HCV.

Changing etiology and epidemiology of hepatocellular carcinoma: Asia and worldwide.

Approximately 80% of hepatocellular carcinoma (HCC) cases arise in sub-Saharan Africa and Eastern Asia, following a similarly high prevalence of chronic hepatitis B virus (HBV) carriers in these regions. The etiology and epidemiology of HCC have recently changed worldwide. Although HBV infection is the main contributor to HCC development, a slow but continuous decline in HBV infection rates has been reported since 1990. Owing to the widespread use of direct-acting antivirals, the incidence of hepatitis C virus-related HCC has remarkably decreased in Japan and European countries. In Korea, Taiwan, and Singapore, the incidence of HBV-related HCC has significantly decreased owing to vaccination against HBV. Globally, while HBV accounted for more than half of HCCs in 1990, this had decreased to 42% in 2019. In contrast, the proportion of patients with alcoholic- and nonalcoholic steatohepatitis (NASH) increased from 13% to 18% and from 5% to 6%, respectively. NASH-related HCC has characteristics that differ from those of virus-associated HCC. Compared with other etiologies, patients with NASHassociated HCC are older, have a higher body mass index, and have higher rates of type 2 diabetes mellitus, hypertension, hyperlipidemia, and cardiovascular disease. Nonalcoholic fatty liver disease (NAFLD)-associated HCC is also known to develop in the absence of cirrhosis, unlike alcohol-related and autoimmune liver diseases. Because patients with NAFLD usually have diabetes or obesity, surveying this population is challenging. Optimal selection of the target population and surveillance tools among patients with NAFLD needs to be determined.

In Vitro Combinatorial Activity of Direct Acting Antivirals and Monoclonal Antibodies against the Ancestral B.1 and BQ.1.1 SARS-CoV-2 Viral Variants.

Combination antiviral therapy may be helpful in the treatment of SARS-CoV-2 infection; however, no clinical trial data are available, and combined use of direct-acting antivirals (DAA) and monoclonal antibodies (mAb) has been reported only anecdotally. To assess the cooperative effects of dual drug combinations in vitro, we used a VERO E6 cell-based in vitro system with the ancestral B.1 or the highly divergent BQ.1.1 virus to test pairwise combinations of the licensed DAA, including nirmatrelvir (NRM), remdesivir (RDV) and the active metabolite of molnupiravir (EIDD-1931) as well the combination of RDV with four licensed mAbs (sotrovimab, bebtelovimab, cilgavimab, tixagevimab; tested only with the susceptible B.1 virus). According to SynergyFinder 3.0 summary and weighted scores, all the combinations had an additive effect. Within DAA/DAA combinations, paired scores with the B.1 and BQ.1.1 variants were comparable. In the post hoc analysis weighting synergy by concentrations, several cases of highly synergistic scores were detected at specific drug concentrations, both for DAA/DAA and for RDV/mAb combinations. This was supported by in vitro confirmation experiments showing a more than a linear shift of a drug-effective concentration (IC50) at increasing concentrations of the companion drug, although the effect was prominent with DAA/DAA combinations and minimal or null with RDV/mAb combinations. These results support the cooperative effects of dual drug combinations in vitro, which should be further investigated in animal models before introduction into the clinic.

Validation of nuclear receptor RORγ isoform 1 as a novel host-directed antiviral target based on the modulation of cholesterol levels

Currently, the clinically approved repertoire of antiviral drugs predominantly comprises direct-acting antivirals (DAAs). However, the use of DAAs is frequently limited by adverse effects, restriction to individual virus species, or the induction of viral drug resistance. These issues will likely be resolved by the introduction of host-directed antivirals (HDAs) targeting cellular proteins crucial for viral replication. However, experiences with the development of antiviral HDAs and clinical applications are still in their infancy. With the present study, we explored the human nuclear receptor and transcription factor RORγ isoform 1 (RORγ1), a member of the retinoic acid receptor-related orphan receptor (ROR) family, as a putative target of antiviral HDAs. To this end, cell culture models were used to investigate major viral human pathogens, i.e. the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human cytomegalovirus (HCMV), varicella zoster virus (VZV) and human immunodeficiency virus 1 (HIV-1). Our results demonstrated (i) an antiviral activity of the clinically relevant RORγ modulators cedirogant and others, (ii) that isoform RORγ1 acts as the responsible determinant and drug target in the analyzed cell culture-based models, (iii) a selectivity of the antiviral effect for RORγ1 over related receptors RORα and RORβ, (iv) a late-phase inhibition exerted by cedirogant in HCMV replication and (v) a mechanistic link to the cellular cholesterol biosynthesis. Combined, the data highlight this novel RORγ-specific antiviral targeting concept and the developmental potential of RORγ-directed small molecules.

SARS-CoV-2 genomics and impact on clinical care for COVID-19.

The emergence and worldwide spread of SARS-CoV-2 during the COVID-19 pandemic necessitated the adaptation and rapid deployment of viral WGS and analysis techniques that had been previously applied on a more limited basis to other viral pathogens, such as HIV and influenza viruses. The need for WGS was driven in part by the low mutation rate of SARS-CoV-2, which necessitated measuring variation along the entire genome sequence to effectively differentiate lineages and characterize viral evolution. Several WGS approaches designed to maximize throughput and accuracy were quickly adopted by surveillance labs around the world. These broad-based SARS-CoV-2 genomic sequencing efforts revealed ongoing evolution of the virus, highlighted by the successive emergence of new viral variants throughout the course of the pandemic. These genomic insights were instrumental in characterizing the effects of viral mutations on transmissibility, immune escape and viral tropism, which in turn helped guide public health policy, the use of monoclonal antibody therapeutics and vaccine development strategies. As the use of direct-acting antivirals for the treatment of COVID-19 became more widespread, the potential for emergence of antiviral resistance has driven ongoing efforts to delineate resistance mutations and to monitor global sequence databases for their emergence. Given the critical role of viral genomics in the international effort to combat the COVID-19 pandemic, coordinated efforts should be made to expand global genomic surveillance capacity and infrastructure towards the anticipation and prevention of future pandemics.

Regional Differences in Clinical Presentation and Prognosis of Patients With Post–Sustained Virologic Response Hepatocellular Carcinoma

Widespread use of direct-acting antivirals for hepatitis C virus infection has been paralleled with increased numbers of patients with hepatocellular carcinoma (HCC) after achieving sustained virologic response (post-SVR HCC) worldwide. Few data compare regional differences in the presentation and prognosis of patients with post-SVR HCC. We identified patients with advanced fibrosis (F3/F4) who developed incident post-SVR HCC between March 2015 and October 2021 from 30 sites in Europe, North America, South America, the Middle East, South Asia, East Asia, and Southeast Asia. We compared patient demographics, liver dysfunction, and tumor burden by region. We compared overall survival by region using Kaplan-Meier analysis and identified factors associated with survival using multivariable Cox regression analysis. Among 8796 patients with advanced fibrosis or cirrhosis who achieved SVR, 583 (6.6%) developed incident HCC. There was marked regional variation in the proportion of patients detected by surveillance (range: 59.5%-100%), median maximum tumor diameter (range, 1.8-5.0 cm), and the proportion with multinodular HCC (range, 15.4%-60.8%). The prognosis of patients highly varied by region (hazard ratio range, 1.82-9.92), with the highest survival rates in East Asia, North America, and South America, and the lowest survival rates in the Middle East and South Asia. After adjusting for geographic region, HCC surveillance was associated with early stage detection (Barcelona Clinic Liver Cancer stage 0/A, 71.0% vs 21.3%; P < .0001) and lower mortality rates (adjusted hazard ratio, 0.29; 95% CI, 0.18-0.46). Clinical characteristics, including early stage detection, and prognosis of post-SVR HCC differed significantly across geographic regions. Surveillance utilization appears to be a high-yield intervention target to improve prognosis among patients with post-SVR HCC globally.

#4237 EFFICACY AND TOLERABILITY OF DIRECT-ACTING ANTIVIRALS IN HEMODIALYSIS PATIENTS WITH CHRONIC HEPATITIS C

Abstract Background and Aims Hepatitis C virus (HCV) infection is common in hemodialysis (HD) patients and is associated with increased morbidity and mortality. In recent years major progress in the treatment of HCV infection has been made with the entry into use of direct-acting antivirals (DAA), which target viral proteins, leading to increases in sustained virological response (SVR) and a marked decrease in side effects. The aim of the study was to evaluate the efficacy and frequency of side-effects of DAA therapy in HD patients with HCV infection. Method The multicentric prospective cohort study included 42 HD patients with HCV infection over the last two years. DAAs therapy was administered according to HCV genotype and drug interactions considering guidelines for a period of 12 weeks (for HCV genotype 1: Elbasvir/Grazoprevir or Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir, and for HCV genotype 4: Elbasvir/Grazoprevir or Ombitasvir/Paritaprevir/Ritonavir). The following clinical parameters at weeks 0, 4, 8, 12, and 24 (12 weeks after the completion of treatment with DAA) were analyzed: presence of side effects, PCR HCV titer (ref. range: &amp;lt;12 IU/ml negative), hemoglobin (Hgb-g/L), epoetin dose (IU/kg/week), alanine aminotransferase level (ALT-U/L), and gamma-glutamyl transferase level (GGT-U/L). Before treatment with DAA liver fibrosis score (F0-F4) was defined by Fibroscan and the patients with liver stiffness over 12,5 kPa (Fibrosis score F4) were considered cirrhotic, but only patients with compensated cirrhosis (Child-Pugh score class A) were treated. For statistical analysis chi-square test and combined analysis of variance for repeated measures were performed by IBM SPSS softver. PCR HCV titer was analyzed with logarithmic transformation of data. Results Over the observed period 42 HD patients with HCV infection (25M and 17F) with the average age 56,78±11,6 years and average HD vintage 159±75 months were included in the study. Twenty-six patients (61,9%) were with HCV genotype 1 and 16 patients (38,1%) with HCV genotype 4. Ten patients (23,8%) were with compensated cirrhosis (F4 fibrosis score by Fibroscan). Three patients (7,1%) had mild gastrointestinal side effects and only one patient (2,4%) discontinuated the therapy during the first week due to intolerancy to DAA. All 41 patients (100%) who completed 12 weeks DAA therapy were PCR HCV negative at 4 weeks of treatment and achieved rapid virological response (RVR) and 12 weeks after the completion of treatment and achieved sustained virological response (SVR12) that was statistically significant (p&amp;lt;0.001). In regard to PCR HCV titer before DAA therapy there was no statistically significant difference among HD patients according to cirrhotic status and HCV genotype. There was no statistically significant change of hemoglobin level and epoetin dose in HD patients during the DAA therapy. The ALT and GGT levels statistically significantly decreased at weeks 12 and 24 compared to week 0 in all treated patients with DAA (ALTweek0 = 35,2±21,7; ALTweek12 = 21,8±16,2; ALTweek24 = 23,5±13,1; p&amp;lt;0.001 and GGTweek0 = 53,3±67; GGTweek12 = 18,6±6,8; GGTweek24 = 19,4±11,5; p = 0.042 respectively). The therapy with DAA was equally effective in patients with compensated cirrhosis and in patients without cirrhosis and there was statistically significant decrease of ALT and GGT levels in both groups of patients (p = 0.002 and p&amp;lt;0.05 respectively). In regard to HCV genotype DAA were equally effective in patients with HCV genotype 1 and in patients with HCV genotype 4 and ALT and GGT levels significantly decreased in both groups of patients (p&amp;lt;0.001 and p&amp;lt;0.05 respectively). Conclusion The therapy with DAA in HD patients with HCV infection was extremely effective and SVR12 was achieved in 100% of treated patients. The administered DAA were equally effective in patients with compensated cirrhosis and in patients without cirrhosis, and in patients with HCV genotype 1 and HCV genotype 4. The therapy with DAA was well tolerated, 7,1% of patients had mild side effects and 2,4% of patients discontinuated the therapy due to intolerance.

Treatment of chronic hepatitis C virus infection to increase access to cancer clinical trials in patients with hematologic malignancies: A prospective observational study.

3142 Background: Most cancer patients with chronic hepatitis C virus (HCV) infection are excluded from cancer clinical trials (CCTs). The use of direct-acting antivirals (DAAs) to eradicate HCV and allow access to CCTs in HCV-infected cancer patients has not been studied. We aimed to evaluate the efficacy and safety of DAA treatment to increase access to CCTs in patients with chronic HCV infection and hematologic malignancies (HM). Methods: HCV-infected patients with HM seen at MD Anderson Cancer Center between 01/01/2016 and 01/31/2023 were enrolled in a prospective observational study. Those initially excluded from CCTs and then treated with DAAs to allow that cancer treatment were further analyzed (cases). HCV-infected cancer patients treated with DAAs but never enrolled in CCTs were used as controls. The 1:1 matching between cases and controls was based on the cancer type and stage, history of &gt; 3 types of chemotherapy, and presence of cirrhosis. The primary outcomes were the efficacy and safety of DAAs. The secondary outcomes were overall survival (OS) and progression-free survival (PFS). Results: Twenty-four patients with HM initially excluded from CCTs because of HCV were enrolled. Twelve of them (50%) received DAAs to have access to CCTs and they were matched to 12 controls. Most of the cases were men (10; 83%), white (6; 50%), non-cirrhotic (10; 83%), and with HCV genotype 1 (9; 75%). Most patients in the control group were men (7; 58%), white (9; 75%), non-cirrhotic (8; 67%), and with HCV genotype 1 (9; 75%). Among the entire study group, adverse events occurred in 6 of the 24 patients (25%), and all were grade 1-2. No HCV-associated liver failure or death occurred. The overall sustained virologic response (microbiologic cure) after completion of antiviral therapy was 92%. Median OS was 74 months in the cases vs 52 months in the controls, median PFS was 30 months in the cases vs 33 months in the controls. When compared to controls in multivariate analysis, cases had significantly better OS (hazard ratio = 0.23, 95% CI = 0.06 to 0.85, p = 0.027). No significant differences were noted in PFS (p=0.13). Death due to progressive HM occurred in all 12 controls (100%) but only in 4 cases (33%) (p=0.001). Conclusions: DAA treatment increases access to CCTs and improves OS in patients with chronic HCV infection and HM. HCV infection should not be considered a contraindication to investigational cancer treatment. The use of DAAs to facilitate access CCTs could become one of the most common indications for DAAs in HCV-infected cancer patients.

Management of dialysis patients with hepatitis C virus in the era of direct-acting antiviral therapy.

The clinical use of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection has dramatically changed management of patients with HCV liver disease since 2014; this is also true for patients undergoing dialysis. Due to the high tolerability and antiviral efficacy of anti-HCV therapy, most dialysis patients with HCV infection should currently be candidates for this treatment. Many patients with HCV antibodies no longer have HCV infection, and it is difficult to identify patients with actual HCV infection based only on HCV antibody assays. Despite the high rate of successful HCV eradication, the risk of liver-related events such as hepatocellular carcinoma (HCC), the major complication of HCV infection, persists even after HCV cure, and patients at risk of HCC should undergo continuous HCC surveillance. Finally, the rarity of HCV reinfection and the survival benefit of HCV eradication in dialysis patients should be explored in further studies.

DAA - directly acting antivirals - as a new, more efficient solution of the chronic hepatitis C treatment and theirs various application.

Introduction Cirrhosis is a condition in which the liver becomes fibrotic following damage to the liver and transforms the architecture of the organ into regenerative nodules. The disease is caused 30% by HCV infection, resulting in a risk of severe complications and death. Since the use of direct-acting antivirals ( DAAs) for the treatment of chronic HCV, sustained virological response (SVR) rates have begun to increase, even in treatment-resistant cases. Studies have also shown that DAAs may have applications in other viral diseases and even In the treatment of breast cancer. Aim of the study The purpouse of our study was to review scientific articles to show the efficiency and potential use of DAAs in the treatment of chronic HCV, and to identify possible directions for further research. Methods and materials We reviewed the English literature in the PubMed, using the key words: "simeprevir" ; "sofosbuvir" ; "velpatasvir" ; "telaprevir" ; "chronic hepatitis C". Results Studies have shown that the therapeutic regimens currently being designed with (DAAs) offer the possibility of treating almost the entire population with hepatitis C, while reducing side effects of interferon therapy such as increased AST, ALT activities, diarrhoea, vomiting, nausea and depression. They remain effective and tolerable, regardless of the stage of cirrhosis and associated serious co-morbidities. Analysis of studiem shows, that DAAs also show efficacy against other disease such as breast cancer, MRSA infections, SARS-CoV-2 or flavivirus infection. Conclusion All (DAAs) are effective in the treatment of patients with HCV, including cirrhosis. They result in significant improvements in prognosis and clinical outcomes. Promising results have been obtained in published data on the effect of DAAs against disease entities other than HCV, suggesting the rationale for future clinical trials to further the hypothesis of the increased potential of these drugs.

Review of heart transplantation from hepatitis C-positive donors.

Significant scarcity of a donor pool exists for heart transplantation (HT) as the prevalence of patients with end-stage refractory heart failure is increasing exceptionally. With the discovery of effective direct-acting antiviral and favorable short-term outcomes following HT, the hearts from hepatitis C virus (HCV) patient are being utilized to increase the donor pool. Short-term outcomes with regards to graft function, coronary artery vasculopathy, and kidney and liver disease is comparable in HCV-negative recipients undergoing HT from HCV-positive donors compared to HCV-negative donors. A significant high incidence of donor-derived HCV transmission was observed with great success of achieving sustained viral response with the use of direct-acting antivirals. By accepting HCV-positive organs, the donor pool has expanded with younger donors, a shorter waitlist time, and a reduction in waitlist mortality. However, the long-term outcomes and impact of specific HCV genotypes remains to be seen. We reviewed the current literature on HT from HCV-positive donors.

Selection dynamics of HCV genotype 3 resistance-associated substitutions under direct-acting antiviral therapy pressure.

The chronic hepatitis C (CHC) treatment is currently based on the use of direct-acting antivirals (DAAs), and patients infected with hepatitis C virus genotype 3 (GT3) have emerged as a more difficult-to-cure population. The NS5A inhibitor daclatasvir (DCV) and sofosbuvir (SOF), an NS5B viral polymerase inhibitor, are among the drugs that compose more effective and safer treatment regimens. The virus genetic variability is related to resistance-associated substitutions (RASs) that adversely impact DAAs effectiveness. The aims of this study were to analyze the association of NS5A and NS5B RASs and other clinical factors with DAAs regimens effectiveness in patients with GT3 CHC infection. This was a prospective cohort study performed in a Brazilian university hospital. Individuals older than 18 years with GT3 CHC treated with SOF+DCV ± ribavirin (RBV) or SOF+peginterferon (PEG)+RBV were included. Blood samples were collected at baseline and post-treatment. A total of 121 patients were included. Sustained virological response rates were 87.6% for the SOF+DCV ± RBV group and 80.0% for the SOF+PEG+RBV arm. Cirrhosis, prior treatment with interferon/PEG+RBV, and baseline NS5A RAS were associated with higher risk of treatment failure. The NS5A analysis suggested that A30K, Y93H, and RAS at site 62 were related to failure. Interestingly, a likely compensatory effect was shown between A30K and A62T. Emergence of Y93H was always associated with RAS at position 62. The RASs dynamics comprehension is an important tool to indicate more effective treatment for GT3 patients.

Cost-effectiveness of direct-acting antivirals for chronic hepatitis C virus in the United States from a payer perspective.

BACKGROUND: Direct-acting antivirals (DAAs) have been a breakthrough therapeutic innovation in the treatment of chronic hepatitis C virus (HCV) with significantly improved efficacy, safety, and tolerability. OBJECTIVE: To evaluate the cost-effectiveness of treating patients with HCV with DAAs compared with pre-DAAs or no treatment over a lifetime horizon from the perspective of the US Veterans Affairs (VA) health care system. METHODS: A hybrid decision-tree and Markov model simulated the health outcomes of a cohort of 142,147 patients with HCV with an average age of 63 years. Demographic data, treatment rates and distribution, treatment efficacy by subpopulation, and health state costs were sourced from VA data. Treatment costs and utility values were sourced from publicly available databases and prior publications for older regimens. RESULTS: Over a lifetime horizon, the use of DAAs results in a significant reduction in advanced liver disease events compared with pre-DAA and no treatment. Total cost savings of $7 and $9 billion over a lifetime horizon (50 years) were predicted for patients who received DAA treatments compared with patients treated with pre-DAA treatments and those who were untreated, respectively. Cost savings were achieved quickly after treatment, with DAAs being inexpensive when compared with both the pre-DAA and untreated scenarios within 5 years. The DAA intervention dominated (ie, more effective and less costly) for both the pre-DAA and untreated strategies on both a per-patient and cohort basis. CONCLUSIONS: The use of DAA-based treatments in patients with HCV in the VA system significantly reduced long-term HCV-related morbidity and mortality, while providing cost savings within only 5 years of treatment. DISCLOSURES: This work was supported by Gilead Inc. Health Economic Outcomes Research group, grant number GS-US-18-HCV003. Drs Yehoshua and Kaushik are employees of Gilead in the Health Economic Outcome Research group. These individuals reviewed the manuscript but did not contribute to input or output of the Markov model. Maple Health Group (Dr El-Moustaid, Ms Raad, and Dr Smith) are consultants hired by Gilead for Markov modeling expertise. The model used in this study was previously published and peer reviewed. Data inputted into the model related to patient demographic, treatment outcomes, clinical outcomes, and costs were completely independent in derivation by Drs Kaplan, Serper, and Durkin and were not influenced by the funding sponsor. Dr Kaplan reports grants from Gilead Inc. during the conduct of the study and grants from Gilead Inc., other from Glycotest Inc., other from AstraZeneca, other from Exact Sciences, and other from Bayer outside the submitted work.

Drug-drug interactions between antithrombotics and direct-acting antivirals in hepatitis C virus (HCV) patients: A brief, updated report.

Hepatitis C virus (HCV) is one of the leading causes of chronic liver disease affecting over 71 million people worldwide. An increased incidence of atherothrombotic events [e.g. coronary artery disease (CAD), atrial fibrillation (AF)] has been observed in HCV seropositive patients. On the other hand, an increased bleeding risk is another clinical issue, particularly in subjects with liver cirrhosis, gastroesophageal varices, portal hypertension, thrombocytopenia and alcohol consumption. The introduction and progressively greater use of direct-acting antivirals (DAAs) (instead of protease and polymerase inhibitors) during the last decade has enabled a sustained virological response to be achieved in a significant percentage of patients. However, due to the high cardiovascular risk profile in HCV-infected patients, the concomitant use of antithrombotic therapies is often required, bearing in mind the possible contraindications. For example, despite better pharmacokinetic and pharmacodynamic properties compared with vitamin K-antagonists, plasma level fluctuations of direct oral anticoagulants (DOACs) due to pathological conditions (e.g. chronic kidney diseases or hepatic cirrhosis) or drug-drug interactions (DDIs) may be of great importance as regards their safety profile and overall clinical benefit. We aimed to examine and briefly summarize the significant DDIs observed between antithrombotic and HCV antiviral drugs.

Pan-genotypic direct-acting antivirals for patients with hepatitis C virus infection and chronic kidney disease stage 4 or 5.

Hepatitis C virus (HCV) infection is a major health problem with significant clinical and economic burdens in patients with chronic kidney disease (CKD) stage 4 or 5. Current guidelines recommend pan-genotypic direct-acting antivirals (DAAs) to be the first-line treatment of choice for HCV. This review summarizes the updated knowledge regarding the epidemiology, natural history, public health perspectives of HCV in patients with CKD stage 4 or 5, including those on maintenance dialysis, and the performance of pan-genotypic DAAs in these patients. The prevalence and incidence of HCV are much higher in patients with CKD stage 4 or 5 than in the general population. The prognosis is compromised if HCV patients are left untreated regardless of kidney transplantation (KT). Following treatment-induced HCV eradication, patient can improve the health-related outcomes by maintaining a long-term aviremic state. The sustained virologic response (SVR12) rates and safety profiles of pan-genotypic DAAs against HCV are excellent irrespective of KT. No dose adjustment of pan-genotypic DAAs is required across CKD stages. Assessing drug–drug interactions (DDIs) before HCV treatment is vital to secure on-treatment safety. The use of prophylactic or preemptive pan-genotypic DAAs in HCV-negative recipients who receive HCV-positive kidneys has shown promise in shortening KT waiting time, achieving excellent on-treatment efficacy and safety, and maintaining post-KT patient and graft survival. HCV elimination is highly feasible through multifaceted interventions, including mass screening, treatment scale-up, universal precautions, and post-SVR12 reinfection surveillance.

Real-Life Early Anthropometric, Lipid and Liver Changes after Direct-Acting Antiviral Therapy in PLWHIV with HCV Co-Infection.

Treatment with interferon-free direct-acting antivirals (DAA) has become the gold standard in chronic hepatitis C virus (HCV) infection. Nevertheless, little research about the metabolic impact of achieving sustained virological response (SVR) is available in HCV/HIV co-infected patients. This research aimed to evaluate early anthropometric, lipid and liver parameters changes after achieving SVR 12 weeks after treatment (SVR12). A real-life retrospective descriptive before-after study assessed 128 DAA treatment episodes from 2015 to 2019 in HCV/HIV co-infected patients. Anthropometric parameters (weight, body mass index), lipid profile, genotype (GT) and viral load, liver data (basics laboratory necroinflammatory parameters and transient elastography (TE)) were collected before treatment with DAA (baseline), and when SVR12 was achieved. Significant increases (p < 0.01) were found in the early lipid profile, measured by LDLc (84.6 ± 35.0 vs. 108.6 ± 35.1 mg/dL) and total cholesterol (161.3 ± 41.0 vs. 183.3 ± 41.6 mg/dL). Significant changes (p < 0.05) were found in liver parameters, measured by ALT (58.2 ± 34.0 vs. 22.0 ± 16.0 U/L), bilirubin (0.8 ± 0.6 vs. 0.6 ± 0.5 mg/dL), albumin (4.2 ± 0.4 vs. 4.3 ± 0.3 g/dL) and liver stiffness (LS) (13.7 ± 13.3 vs. 11.8 ± 12.1 kPa). The main conclusions were that the use of DAA has an early negative impact on lipid metabolism. Achieving SVR12 against HCV leads to an early improvement in liver function and LS in HCV/HIV co-infected patients without interference with antiretroviral treatment (ART) and DAA. Short-term close lipid monitoring may be necessary when combining protease inhibitors. HCV-GT-3/HIV co-infected patients might require further close monitoring for residual fibrosis. These findings can be relevant for actual clinical practice.