Combination Of Direct-acting Antiviral Agents Research Articles

Therapeutic Intervention of Serine Protease Inhibitors against Hepatitis C Virus.

Hepatitis C virus (HCV) is a globally prevalent and hazardous disorder that is responsible for inducing several persistent and potentially fatal liver diseases. Current treatment strategies offer limited efficacy, often accompanied by severe and debilitating adverse effects. Consequently, there is an urgent and compelling need to develop novel therapeutic interventions that can provide maximum efficacy in combating HCV while minimizing the burden of adverse effects on patients. One promising target against HCV is the NS3-4A serine protease, a complex composed of two HCV-encoded proteins. This non-covalent heterodimer is crucial in the viral life cycle and has become a primary focus for therapeutic interventions. Although peginterferon, combined with ribavirin, is commonly employed for HCV treatment, its efficacy is hampered by significant adverse effects that can profoundly impact patients' quality of life. In recent years, the development of direct-acting antiviral agents (DAAs) has emerged as a breakthrough in HCV therapy. These agents exhibit remarkable potency against the virus and have demonstrated fewer adverse effects when combined with other DAAs. However, it is important to note that there is a potential for developing resistance to DAAs due to alterations in the amino acid position of the NS3-4A protease. This emphasizes the need for ongoing research to identify strategies that can minimize the emergence of resistance and ensure long-term effectiveness. While the combination of DAAs holds promise for HCV treatment, it is crucial to consider the possibility of drug-drug interactions. These interactions may occur when different DAAs are used concurrently, potentially compromising their therapeutic efficacy. Therefore, carefully evaluating and monitoring potential drug interactions are vital to optimize treatment outcomes. In the pursuit of novel therapeutic interventions for HCV, the field of computational biology and bioinformatics has emerged as a valuable tool. These advanced technologies and methodologies enable the development and design of new drugs and therapeutic agents that exhibit maximum efficacy, reduced risk of resistance, and minimal adverse effects. By leveraging computational approaches, researchers can efficiently screen and optimize potential candidates, accelerating the discovery and development of highly effective treatments for HCV, treatments.

Hepatitis C Virus Infection in the Elderly in the Era of Direct-Acting Antivirals: Evidence from Clinical Trials and Real Life.

The introduction of direct-acting antiviral agents (DAAs) into clinical practice has revolutionized the therapeutic approach to patients with chronic hepatitis C virus (HCV) infection. According to the most recent guidelines, the first line of treatment for HCV infection involves the use of one of three pan-genotypic DAA combinations, sofosbuvir/velpatasvir (SOF/VEL), glecaprevir/pibrentasvir (GLE/PIB), and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX). These drugs have been shown to be effective and safe in numerous clinical trials and real-world studies, but special populations have been neglected. Among the special populations to be treated are elderly patients, whose numbers are increasing in clinical practice. The management of these patients can be challenging, in particular due to multiple comorbidities, polypharmacotherapy, and potential drug-drug interactions. This narrative review aims to summarize the current scientific evidence on the efficacy and safety of DAAs in the elderly population, both in clinical trials and in real-life settings. Although there is still a paucity of real-world data and no clinical trials have yet been conducted in the population aged ≥ 75 years old, some considerations about the efficacy and safety of DAAs in the elderly can be made based on the results of these studies. The pan-genotypic associations of DAAs appear to be as efficacious and safe in the elderly population as in the general population; this is both in terms of similar sustained virologic response (SVR) rates and similar frequencies of adverse events (AEs). However, further studies specifically involving this patient population would be necessary to confirm this evidence.

Mechanisms and Clinical Significance of Pharmacokinetic Drug Interactions Mediated by FDA and EMA-approved Hepatitis C Direct-Acting Antiviral Agents.

The treatment of patients infected with the hepatitis C virus (HCV) has been revolutionised by the development of direct-acting antiviral agents (DAAs) that target specific HCV proteins involved in viral replication. The first DAAs were associated with clinical problems such as adverse drug reactions and pharmacokinetic drug-drug interactions (DDIs). Current FDA/EMA-approved treatments are combinations of DAAs that simultaneously target the HCV N5A-protein, the HCV N5B-polymerase and the HCV NS3/4A-protease. Adverse events and DDIs are less likely with these DAA combinations but several DDIs of potential clinical significance remain. Much of the available information on the interaction of DAAs with CYP drug-metabolising enzymes and influx and efflux transporters is contained in regulatory summaries and is focused on DDIs of likely clinical importance. Important DDIs perpetrated by current DAAs include increases in the pharmacokinetic exposure to statins and dabigatran. Some mechanistic information can be deduced. Although the free concentrations of DAAs in serum are very low, a number of these DDIs are likely mediated by the inhibition of systemic influx transporters, especially OATP1B1/1B3. Other DDIs may arise by DAA-mediated inhibition of intestinal efflux transporters, which increases the systemic concentrations of some coadministered drugs. Conversely, DAAs are victims of DDIs mediated by cyclosporin, ketoconazole, omeprazole and HIV antiretroviral drug combinations, especially when boosted by ritonavir and, to a lesser extent, cobicistat. In addition, concurrent administration of inducers, such as rifampicin, carbamazepine and efavirenz, decreases exposure to some DAAs. Drug-drug interactions that increase the accumulation of HCV N3/4A-protease inhibitors like grazoprevir may exacerbate hepatic injury in HCV patients.

Eliminate Hepatitis C as a Public Health Threat: A Narrative Review of Strategies, Gaps, and Opportunities for China.

IntroductionAs a country that is heavily burdened by hepatitis C, China’s successful responses to this public health threat have significant implications for the achievement of the global elimination goal.MethodsThis article reviews China’s strategies for prevention, screening, diagnosis, access to direct-acting antiviral agents (DAA) therapy, and patient management of hepatitis C. It also analyses the major challenges and summarizes the valuable successful international experiences that have implications for China to achieve the elimination goal.ResultsTo promote the achievement of elimination, China has taken a series of proactive measures to promote the prevention and treatment of hepatitis C. Compared with other middle-income countries, there is still much room for China to achieve universal screening, diagnosis and treatment based on a streamlined disease management procedure. A stronger role of primary care in an integrated healthcare delivery system and integration of hepatitis C with other infectious disease programs should also be the focus of China’s efforts.ConclusionsAs a developing country with a large population, a "micro-elimination" strategy with focused screening and proactive diagnosis and treatment for the vulnerable population may be a more practical approach to eliminating hepatitis C in China. Continued efforts are needed to fully overcome the intellectual property barriers of sofosbuvir for forming the more competitive pan-genotype DAA combinations based on the locally developed DAAs. Meanwhile, the safety net for patients in economic hardship needs to be further strengthened. More importantly, it is necessary to promote patients' willingness and compliance with standard treatment through increased awareness of hepatitis C. The development of an integrated healthcare delivery system, a disease management procedure which is suitable for primary care, and full compliance of the primary care providers are also important to achieve effective cascade care management.

Follow-Up of Patients Who Achieved Sustained Virologic Response after Interferon-Free Treatment against Hepatitis C Virus: Focus on Older Patients.

Background and Objectives: Direct-acting antiviral agents (DAAs) have improved sustained virologic response (SVR) rates in patients with chronic hepatitis C virus (HCV) infection. Our aim was to elucidate the occurrence of hepatocellular carcinoma (HCC) and to compare the outcomes of patients aged 75 years or older (older group) with those of patients younger than 75 years (younger group) after SVR. Materials and Methods: Among 441 patients treated with interferon-free DAA combinations, a total of 409 SVR patients were analyzed. We compared the two age groups in terms of HCC incidence and mortality rates. Results: Older and younger groups consisted of 68 and 341 patients, respectively. Occurrence of HCC after SVR did not differ between the two groups of patients with a history of HCC. Occurrence of HCC after SVR was observed more in younger patients without a history of HCC (p < 0.01). Although older patients without a history of HCC had a higher mortality rate (p < 0.01), their causes of death were not associated with liver diseases. Among younger patients without a history of HCC, none died. Conclusions: After SVR, liver disease may not be a prognostic factor in older HCV patients without a history of HCC.

Updated View on Kidney Transplant from HCV-Infected Donors and DAAs.

Background: The discrepancy between the number of potential available kidneys and the number of patients listed for kidney transplant continues to widen all over the world. The transplant of kidneys from hepatitis C virus (HCV)-infected donors into HCV naïve recipients has grown recently because of persistent kidney shortage and the availability of direct-acting antiviral agents. This strategy has the potential to reduce both waiting times for transplant and the risk of mortality in dialysis. Aim: We made an extensive review of the scientific literature in order to review the efficacy and safety of kidney transplant from HCV-viremic donors into HCV naïve recipients who received early antiviral therapy with direct-acting antiviral agents (DAAs). Results: Evidence has been rapidly accumulated on this topic and some reports have been published (n = 11 studies, n = 201 patients) over the last three years. Various combinations of DAAs were administered—elbasvir/grazoprevir (n = 38), glecaprevir/pibrentasvir (n = 110), and sofosbuvir-based regimens (n = 53). DAAs were initiated in a range between a few hours before renal transplant (RT) to a median of 76 days after RT. The sustained virological response (SVR) rate was between 97.5% and 100%. A few severe adverse events (SAEs) were noted including fibrosing cholestatic hepatitis (n = 3), raised serum aminotransferase levels (n = 11), and acute rejection (n = 7). It remains unclear whether the AEs were related to the transmission of HCV, the use of DAAs, or kidney transplant per se. It appears that the frequency of AEs was greater in those studies where DAAs were not given in the very early post-kidney transplant phase. Conclusions: The evidence gathered to date encourages the expansion of the kidney donor pool with the adoption of HCV-infected donor organs. We suggest that kidney transplants from HCV-viremic kidneys into HCV-uninfected recipients should be made in the context of research protocols. Many of the studies reported above were externally funded and we need research generating “real-world” evidence. The recent availability of pangenotypic combinations of DAAs, which can be given even in patients with eGFR < 30/min/1.73 m2, will promote the notion that HCV-viremic donors are a significant resource for kidney transplant.

Real-Life Effectiveness and Safety of Glecaprevir/Pibrentasvir for Korean Patients with Chronic Hepatitis C at a Single Institution.

Background/AimsGlecaprevir/pibrentasvir (G/P) is a combination of direct-acting antiviral agents that is an approved treatment for chronic infections by all six hepatitis C virus (HCV) genotypes. However, there are limited data on the effect of G/P in Korean patients in actual real-world settings. We evaluated the real-life effectiveness and safety of G/P at a single institution in Korea.MethodsThis retrospective, observational, cohort study used sustained virologic response at 12 weeks after treatment completion (SVR12) as the primary effectiveness endpoint. Safety and tolerability were also determined.ResultsWe examined 267 individuals who received G/P for chronic HCV infections. There were 148 females (55.4%), and the overall median age was 63.0 years (range, 25 to 87 years). Eighty-three patients (31.1%) had HCV genotype-1 and 182 (68.2%) had HCV-2. A total of 212 patients (79.4%) were HCV treatment-naïve, 200 (74.9%) received the 8-week treatment, 13 (4.9%) had received prior treatment for hepatocellular carcinoma, 37 (13.7%) had chronic kidney disease stage 3 or higher, and 10 (3.7%) were receiving dialysis. Intention to treat (ITT) analysis indicated that 256 (95.9%) achieved SVR12. A modified ITT analysis indicated that SVR12 was 97.7% (256/262). Six patients failed therapy because of posttreatment relapse. SVR12 was significantly lower in those who received prior sofosbuvir treatment (p=0.002) and those with detectable HCV RNA at week 4 (p=0.027). Seventy patients (26.2%) experienced one or more adverse events, and most of them were mild.ConclusionsThese real-life data indicated that G/P treatment was highly effective and well tolerated, regardless of viral genotype or patient comorbidities. (Gut Liver 2021;15-450)

Direct-acting antiviral agents in lymphoproliferative disorders: more complex than expected.

Direct-acting antiviral agents in lymphoproliferative disorders: more complex than expected.

Immunological Dynamics Associated with Direct-Acting Antiviral Therapies in Naive and Experimented HCV Chronic-Infected Patients.

The therapeutic strategies used in the treatment of hepatitis C are essentially based on the combination of direct-acting antiviral agents (DAAs). This therapy has been shown to be very effective in relation to patient adherence to treatment and has shown high rates of sustained virological response (SVR). However, the immunological dynamics of patients infected with HCV is poorly understood. This fact led us to investigate the immune system of naive and experienced patients, who we followed before the therapy and three months after the end of treatment. In this study, 35 naive and experienced Brazilian patients with chronic hepatitis C and 50 healthy donors (HD group) were studied. The analysis of the soluble immunological biomarkers was performed using the flow cytometry methodology. The SVR rate was >90% among the 35 patients. Before treatment, correlations in the naive HCV group demonstrated a mix of inflammatory response occurring with moderate correlations between chemokines, inflammatory cytokines, and Th2 profile, with a strong regulation between IL-10 and IL-17A. On the other hand, experienced patients demonstrated a poor interaction between cytokines, chemokines, and cells with a strong correlation between IL-10, IL-6, CXCL-10, and CD8+ besides the interactions between IFN-γ and IL-4. Furthermore, naive and experienced patients seem to have a distinct soluble biomarker profile; therefore, a long-term follow-up is needed to evaluate patients treated with DAAs.

Comparative Study between Efficacy of Two Quadruple DAAs Therapy in Treatment of HCV Relapsers

Background: Chronic hepatitis C virus (HCV) is considered as a major cause of liver diseases. The standard treatment of HCV infection is a combination of direct-acting antiviral agents (DAAs). Relapse is defined where HCV RNA remained undetectable at the end of therapy but rebounded to pretreatment levels once DAA therapy was discontinued. Aim of the study: This study was performed to compare efficacy and safety of two quadruple DAAs regimens (Sofosbuvir/Daclatasvir/Simeprevir and Ribavirin Vs. Sofosbuvir/Ombitasvir/ Paritaprevir/ ritonavir - Ribavirin) in treatment of HCV relapsers. Patients and Methods: Retrospective cross-sectional study of 90 experienced patients previously treated with Sofosbuvir and Daclatasvir ± Ribavirin for 3 months and relapsed. The patients were divided into two groups, each group included 45 patients: Group I treated with (Sofosbuvir and Daclatasvir -simeprevir—Ribavirin) while Group II treated with (Sofosbuvir-Ombitasvir/Paritaprevir/ritonavir - Ribavirin). Results: The study showed an excellent response to both regimens of treatment. In group I; the sustained virologic response rates at 24th week were 44/45 (97.8%); 100% (29/29) in non-cirrhotic and 93.8% (15/16) in cirrhotic patients. while group II SVR 24 rates were 93.3% (44/45); 92.9% (26/28) of non-cirrhotic patients, and 94.1% (16/17) of cirrhotic patients. while group II SVR 24 93.3% (44/45) of overall patients, 92.9% (26/28) of non-cirrhotic patients, and 94.1% (16/17) of cirrhotic patients. Additionally, the most common adverse events reported were easy fatiguability, headache, nausea, generalized weakness, photosensitivity - in group I only. Conclusion: It could be concluded that the current combination regimen is well tolerated and achieved excellent SVR rates.

Comparative Study between Efficacy of Two Quadruple DAAs Therapy in Treatment of HCV Relapsers

Background: Chronic hepatitis C virus (HCV) is considered as a major cause of liver diseases. The standard treatment of HCV infection is a combination of direct-acting antiviral agents (DAAs). Relapse is defined where HCV RNA remained undetectable at the end of therapy but rebounded to pretreatment levels once DAA therapy was discontinued. Aim of the study: This study was performed to compare efficacy and safety of two quadruple DAAs regimens (Sofosbuvir/Daclatasvir/Simeprevir and Ribavirin Vs. Sofosbuvir/Ombitasvir/ Paritaprevir/ ritonavir - Ribavirin) in treatment of HCV relapsers. Patients and Methods: Retrospective cross-sectional study of 90 experienced patients previously treated with Sofosbuvir and Daclatasvir ± Ribavirin for 3 months and relapsed. The patients were divided into two groups, each group included 45 patients: Group I treated with (Sofosbuvir and Daclatasvir -simeprevir—Ribavirin) while Group II treated with (Sofosbuvir-Ombitasvir/Paritaprevir/ritonavir - Ribavirin). Results: The study showed an excellent response to both regimens of treatment. In group I; the sustained virologic response rates at 24th week were 44/45 (97.8%); 100% (29/29) in non-cirrhotic and 93.8% (15/16) in cirrhotic patients. while group II SVR 24 rates were 93.3% (44/45); 92.9% (26/28) of non-cirrhotic patients, and 94.1% (16/17) of cirrhotic patients. while group II SVR 24 93.3% (44/45) of overall patients, 92.9% (26/28) of non-cirrhotic patients, and 94.1% (16/17) of cirrhotic patients. Additionally, the most common adverse events reported were easy fatiguability, headache, nausea, generalized weakness, photosensitivity - in group I only. Conclusion: It could be concluded that the current combination regimen is well tolerated and achieved excellent SVR rates.

Hepatitis C treatment with all-oral direct-acting antivirals: Effectiveness and tolerance in a multicenter, prospective, observational study from French general hospitals (APROVVIE, ANGH)

According to clinical trials, the treatment of patients with chronic hepatitis C (CHC) with second-generation direct acting antiviral agents (DAAs) is highly efficient and well tolerated. The goal of this study was to investigate the effectiveness and safety of various combinations of these drugs during their first 2 years of use in the real-world practice of French general hospitals. Data from patients treated with all-oral DAAs in 24 French non-academic hospital centers from March 1, 2014 to January 1, 2016, were prospectively recorded. The sustained virological response 12-24 weeks after treatment (SVR 12-24) was estimated and severe adverse events (SAE) were evaluated and their predictive factors were determined using logistic regression. Data from 1123 patients were analyzed. The population was 69% genotype (G) 1, 13% G3, 11.5% G4, 5% G2, 49% with cirrhosis and 55% treatment-experienced. The treatment regimens were sofosbuvir/ledipasvir (38%), sofosbuvir/daclatasvir (32%), sofosbuvir/simeprevir (17%), ombitasvir+paritaprevir+ritonavir (5%) (with dasabuvir 3.5%), and sofosbuvir/ribavirin (8%). Ribavirin was given to 24% of patients. The SVR 12-24 was 91.0% (95% CI: 89.2-92.5%). Sofosbuvir-ribavirin was less effective than other regimens. The independent predictors of SVR 12-24 by logistic regression were body weight, albumin, previous hepatocellular carcinoma and treatment regimen (sofosbuvir/ribavirin vs. others). Sixty-four severe adverse events (SAE) were observed in 59 [5.6%] patients, and were independently predicted by cirrhosis and baseline hemoglobin. Serum creatinine increased during treatment (mean 8.5%, [P<10-5]), satisfying criteria for acute kidney injury in 62 patients (7.3%). Patient-reported overall tolerance was excellent, and patient-reported fatigue decreased during and after treatment. Second generation DAAs combinations are as effective and well tolerated in a «real-world» population as in clinical trials. Further studies are needed on renal tolerance.

Cost-effectiveness of novel regimens for Chinese patients with chronic hepatitis C

Objective: Direct-acting antiviral agents (DAAs) have been approved for treating hepatitis C virus (HCV) infection in China. However, they are substantially more expensive. The current analysis will investigate the cost-effectiveness of novel regimens compared with pegylated interferon and ribavirin (PR) therapies for informing Chinese decision-makers.Methods: A Markov model was developed to measure economic and health outcomes of novel regimens for genotype 1b, 2, 3, and 6 HCV infections compared with PR treatment. Clinical, cost, and utility inputs were gathered from published sources. Discounted quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs) are shown. The uncertainty was facilitated by one-way and probabilistic sensitivity analyses.Results: For genotype 1b HCV infection, the combination of paritaprevir, ritonavir, ombitasvir and dasabuvir was cost-saving compared with four competing alternatives. The ICERs of sofosbuvir plus ribavirin for genotypes 2 and 3 were lower than the threshold ($18,234/QALY). Among available strategies for patients with genotype 6, sofosbuvir in combination with ribavirin was the cost-saving alternative compared with PR. The results were robust to sensitivity analyses.Conclusions: For both genotype 1b and 6 HCV infections in the context of Chinese patients, there were combinations of DAAs that were cost-saving compared with the usual PR treatment, and cost-effective for genotypes 2 and 3.

Targeting Innate and Adaptive Immune Responses to Cure Chronic HBV Infection

Fewer than 1% of chronic hepatitis B virus infections per year are cured with antiviral treatment. This creates a need for long-term treatment, which poses challenges for patients and health systems. Because cure is accompanied by recovery of antiviral immunity, a combination of direct-acting antiviral agents and immunotherapy are likely to be required. Extensive efforts have been made to identify determinants of the failed immune response to hepatitis B virus in patients with chronic infection. We review mechanisms of immune dysfunction in patients with chronic hepatitis B virus infection, immunotherapy strategies in development, and the challenges associated with successful implementation of immunotherapy.

Grazoprevir/elbasvir treatment for the relapse of HCV genotype 1b infection after ledipasvir/sofosbuvir: A case report.

The treatment of chronic hepatitis C has radically changed due to the development of direct-acting antiviral agents (DAAs). Twelve-week treatment with ledipasvir and sofosbuvir (LDV/SOF), a combination of DAAs, is highly effective in patients with hepatitis C virus (HCV) genotype 1 infection. However, the overall sustained virological response rate 12 weeks after the end of treatment (SVR12) is not 100%. Elbasvir (EBR) combined with grazoprevir (GZR) is the latest approved therapy for patients with genotype 1 or 4 chronic hepatitis C. However, to the best of our knowledge no case reports have described retreatment with GZR/EBR in patients with a history of failed LDV/SOF treatment. The present case report indicated a case in which GZR/EBR was effective for the retreatment of a patient with a history of failed LDV/SOF treatment and chronic hepatitis C. The present study indicated a 55-year-old Japanese male with a history of chronic hepatitis C and compensated liver cirrhosis. The patient exhibited the amino acid mutation Y93H in NS5A. Therefore, treatment with LDV/SOF was initiated, which was effective and suppressed the virus during oral administration. However, 4 weeks after treatment, the patient's viral load relapsed and returned to its original level. After the patient provided informed consent, treatment with GZR/EBR was initiated. No problems related to GZR/EBR were observed during treatment and the patient's SVR12 was evaluated at 12 weeks posttreatment. In conclusion, GZR/EBR treatment was useful for treating a relapse of HCV genotype 1b infection in the present case after LDV/SOF treatment, despite liver fibrosis, in the presence of the high-frequency amino acid mutation Y93H in NS5A. Although it will be necessary to examine a large number of cases, the present findings suggest that GZR/EBR may be a potential treatment option for relapse of HCV genotype 1b infection after LDV/SOF treatment.

Daclatasvir-sofosbuvir combination therapy for chronic hepatitis C virus infection: progress in clinical studies

All-oral, pan-genotypic combination of direct-acting antiviral agents is currently clinically prescribed trends in the management of chronic hepatitis C virus infection. The combination of daclatasvir and sofosbuvir has proven strong antiviral activity across all common genotypes in clinical trials and real world studies. Furthermore, it can be safely used in patients with advanced liver disease, HCV/HIV co-infection, or HCV recurrence after liver transplantation, more patients will gain clinical benefits. We aim to summarize the clinical progress about this combination.

Retreatment of patients with treatment failure of direct-acting antivirals: Focus on hepatitis C virus genotype 1b.

The recent development of direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) infection could lead to higher sustained virological response (SVR) rates, with shorter treatment durations and fewer adverse events compared with regimens that include interferon. However, a relatively small proportion of patients cannot achieve SVR in the first treatment, including DAAs with or without peginterferon and/or ribavirin. Although retreatment with a combination of DAAs should be conducted for these patients, it is more difficult to achieve SVR when retreating these patients because of resistance-associated substitutions (RASs) or treatment-emergent substitutions. In Japan, HCV genotype 1b (GT1b) is founded in 70% of HCV-infected individuals. In this minireview, we summarize the retreatment regimens and their SVR rates for HCV GT1b. It is important to avoid drugs that target the regions targeted by initial drugs, but next-generation combinations of DAAs, such as sofosbuvir/velpatasvir/voxilaprevir for 12 wk or glecaprevir/pibrentasvir for 12 wk, are proposed to be potential solution for the HCV GT1b-infected patients with treatment failure, mainly on a basis of targeting distinctive regions. Clinicians should follow the new information and resources for DAAs and select the proper combination of DAAs for the retreatment of HCV GT1b-infected patients with treatment failure.

Availability of hepatitis C diagnostics and therapeutics in European and Eurasia countries

BackgroundTreatment with direct acting antiviral agents (DAAs) has provided sustained virological response rates in >95% of patients with chronic hepatitis C virus (HCV) infection. However treatment is costly and market access, reimbursement and governmental restrictions differ among countries. We aimed to analyze these differences among European and Eurasian countries. MethodsA survey including 20-item questionnaire was sent to experts in viral hepatitis. Countries were evaluated according to their income categories by the World Bank stratification. ResultsExperts from 26 countries responded to the survey. As of May 2016, HCV prevalence was reported as low (≤1%) in Croatia, Czech Republic, Denmark, France, Germany, Hungary, the Netherlands, Portugal, Slovenia, Spain, Sweden, UK; intermediate (1–4%) in Azerbaijan, Bosnia and Herzegovina, Italy, Kosovo, Greece, Kazakhstan, Romania, Russia, Serbia and high in Georgia (6.7%). All countries had national guidelines except Albania, Kosovo, Serbia, Tunisia, and UK.Transient elastography was available in all countries, but reimbursed in 61%. HCV-RNA was reimbursed in 81%.PegIFN/RBV was reimbursed in 54% of the countries. No DAAs were available in four countries: Kazakhstan, Kosovo, Serbia, and Tunisia. In others, at least one DAA combination with either PegIFN/RBV or another DAA was available. In Germany and the Netherlands all DAAs were reimbursed without restrictions: Sofosbuvir and sofosbuvir/ledipasvir were free of charge in Georgia. ConclusionPrevalence of HCV is relatively higher in lower-middle and upper-middle income countries. DAAs are not available or reimbursed in many Eurasia and European countries. Effective screening and access to care are essential for reducing liver-related morbidity and mortality.

Searching for synergy: Identifying optimal antiviral combination therapy using Hepatitis C virus (HCV) agents in a replicon system

Direct acting antiviral agents (DAAs) are potent inhibitors of Hepatitis C virus (HCV) that have revolutionized the treatment landscape for this important viral disease. There are currently four classes of DAAs that inhibit HCV replication via distinct mechanisms of action: nonstructural protein (NS) 3/4a protease inhibitors, NS5A inhibitors, NS5B nucleoside polymerase inhibitors, and NS5B non-nucleoside polymerase inhibitors. Combination therapy with two or more DAAs has great potential to further enhance antiviral potency. The purpose of this study was to identify optimal combinations of DAAs against genotype 1 HCV replicons that maximized the inhibition of replicon replication. All possible two-drug combinations were evaluated against genotype 1a and 1b HCV replicons using a 96-well plate luciferase-based assay in triplicate. The Greco Universal Response Surface Area mathematical model was fit to the luciferase data to identify drug-drug interactions (i.e.: synergy, additivity, and antagonism) for antiviral effect against both genotypes. This information was used to rank-order combinations of DAAs based on their ability to inhibit replicon replication against genotype 1a and 1b HCV. These preclinical findings can provide information as to which antiviral regimens should move on in the development process.

Efficacy and safety of direct antiviral agents in a cohort of cirrhotic HCV/HIV-coinfected patients.

New direct-acting antiviral agents (DAAs) have shown great efficacy and tolerability in clinical trials and real-life cohorts. However, data are scarce regarding efficacy and safety in cirrhotic HCV/HIV-coinfected patients. A multicentre prospective analysis was performed in 13 Spanish hospitals, including all cirrhotic HCV/HIV-coinfected patients starting DAA combinations from January to December 2015. Sustained virological response 12 weeks after treatment (SVR12) was analysed. Withdrawal due to toxicity and/or hepatic decompensation and change in liver stiffness measurement (LSM) after HCV treatment were evaluated. Patients (n = 170) were mostly male (n = 125; 74.3%) with the following HCV genotype (Gt) distribution: Gt-1a, 68 (40%); Gt-1b, 21 (12.4%); Gt-4, 47 (27.6%); and Gt-3, 26 (15.3%). Baseline median LSM was 20.6 kPa (IQR 16.1-33.7) and log10 HCV-RNA 6.1 IU/mL (IQR 5.7-6.5). Most patients had a Child-Pugh class A score (n = 127; 74.7%) and 28 (16.5%) had prior hepatic decompensation. There were 89 (52.4%) pretreated patients with 40.4% (n = 36) of null responders. Preferred regimens were as follows: sofosbuvir/ledipasvir + ribavirin, 43 (25.3%) patients; sofosbuvir + simeprevir + ribavirin, 34 (20%); sofosbuvir/ledipasvir, 26 (15.3%) and sofosbuvir + daclatasvir + ribavirin, 25 (14.7%). Overall SVR12 was 92.9% (158/170), without differences between genotypes. Pretreated patients had lower SVR12 rates compared with naive (88.8% versus 97.5%; P = 0.026). Treatment failures were as follows: 7 (4.1%) relapses; 2 (1.2%) lost to follow-up; 1 (0.6%) toxicity-related discontinuation; 1 (0.6%) hepatic decompensation; and 1 (0.6%) viral breakthrough. On-treatment hepatic decompensation was recorded in four (2.4%) patients (encephalopathy and ascites, two each). Paired LSM in 33 patients showed a decrease of 5.6 kPa (95% CI 1.8-9.2; P = 0.004). In our cohort of cirrhotic HCV/HIV-coinfected patients, DAAs were highly safe and efficacious. Viral eradication was associated with a significant decrease in liver stiffness.