Current Treatment Of Chronic Hepatitis Research Articles

Toward a Functional Cure for Hepatitis B.

Current treatment of chronic hepatitis B virus (HBV) infection, pegylated interferon-α (pegIFN-α) and nucleos(t)ide analogue (NA), can suppress HBV replication, reverse liver inflammation and fibrosis, and decrease risks of cirrhosis and hepatocellular carcinoma, but hepatitis B surface antigen (HBsAg) loss is rare. Functional HBV cure is defined as undetectable HBsAg and unquantifiable serum HBV DNA for at least 24 weeks after a finite course of therapy. This requires suppression of HBV replication and viral protein production as well as restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. In parallel, immune modulatory therapies to stimulate HBV-specific immune response and to remove immune blockade are being tested. Clinical trials of direct-acting antivirals alone or immune modulatory therapies alone have not been successful in achieving HBV cure. Recent combinations of direct-acting antivirals and immune modulatory therapies have shown promising results particularly with combinations that included pegIFN-α. These results need to be confirmed in larger studies with longer follow-up, and further work is needed to develop simpler regimens with fewer drugs that can be administered orally and safely. While there is a strong desire to develop finite therapies that can achieve HBV cure, safety is paramount and new therapies must provide incremental value compared to standard of care, which is predominantly long-term NA therapy.

Current treatment of chronic hepatitis B: Clinical aspects and future directions.

Hepatitis B virus (HBV) infection is a public health threat worldwide, and there is no direct treatment yet available. In the event of infection, patients may present liver cirrhosis and cancer, which threaten the patients’ health globally, especially in the Asia-Pacific region and China. In 2019, Chinese hepatopathologists updated the 2015 Guidelines for the Prevention and Treatment of Chronic Hepatitis B as the clinical reference. The other versions formulated by the American Association for the Study of Liver Diseases (2018 AASLD guidelines) (AASLD, 2018), European Association for the Study of the Liver (2017 EASL guidelines) (EASL, 2017), and Asian-Pacific Association for the Study of the Liver (2015 APASL guidelines) (APASL, 2015) also provide clinical guidance. However, there are still some issues that need to be addressed. In the present study, the following aspects will be introduced successively: (1) Who should be treated in the general population according to the guidelines; (2) Treatment of specific populations infected with HBV; (3) Controversial issues in clinical practice; (4) Perspective.

Variability in the Responses of Hepatitis B Virus D-Subgenotypes to Antiviral Therapy: Designing Pan-D-Subgenotypic Reverse Transcriptase Inhibitors.

Nucleos(t)ide analogues entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line monotherapies for chronic hepatitis B (CHB). Multiple HBV genotypes/subgenotypes have been described, but their impact on treatment response remains largely elusive. We investigated the effectiveness of ETV/TDF on HBV/D-subgenotypes, D1/D2/D3/D5, studied the structural/functional differences in subgenotype-specific reverse transcriptase (RT) domains of viral polymerase, and identified novel molecules with robust inhibitory activity on various D-subgenotypes. Transfection of Huh7 cells with full-length D1/D2/D3/D5 and in vitro TDF/ETV susceptibility assays demonstrated that D1/D2 had greater susceptibility to TDF/ETV while D3/D5 exhibited poorer response. Additionally, HBV load was substantially reduced in TDF-treated CHB patients carrying D1/D2 but minimally reduced in D3/D5-infected patients. Comparison of RT sequences of D-subgenotypes led to identification of unique subgenotype-specific residues, and molecular modeling/docking/simulation studies depicted differential bindings of TDF/ETV to the active site of their respective RTs. Replacement of signature residues in D3/D5 HBV clones with corresponding amino acids seen in D1/D2 improved their susceptibility to TDF/ETV. Using high throughput virtual screening, we identified N(9)-[3-fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases, including N6-substituted (S)-FPMP derivative of 2,6-diaminopurine (DAP) (OB-123-VK), as potential binders of RT of different D-subgenotypes. We synthesized (S)-FPMPG prodrugs (FK-381-FEE/FK-381-SEE/FK-382) and tested their effectiveness along with OB-123-VK. Both OB-123-VK and FK-381-FEE exerted similar antiviral activities against all D-subgenotypes, although FK-381-FEE was more potent. Our study highlighted the natural variation in therapeutic response of D1/D2/D3/D5 and emphasized the need for HBV subgenotype determination before treatment. Novel molecules described here could benefit future design/discovery of pan-D-subgenotypic inhibitors. IMPORTANCE Current treatment of chronic hepatitis B relies heavily on nucleotide/nucleoside analogs in particular, tenofovir disoproxil fumarate (TDF) and entecavir (ETV) to keep HBV replication under control and prevent end-stage liver diseases. However, it was unclear whether the therapeutic effects of TDF/ETV differ among patients infected with different HBV genotypes and subgenotypes. HBV genotype D is the most widespread of all HBV genotypes and multiple D-subgenotypes have been described. We here report that different subgenotypes of HBV genotype-D exhibit variable response toward TDF and ETV and this could be attributed to naturally occurring amino acid changes in the reverse transcriptase domain of the subgenotype-specific polymerase. Further, we identified novel molecules and also synthesized prodrugs that are equally effective on different D-subgenotypes and could facilitate management of HBV/D-infected patients irrespective of D-subgenotype.

New treatment options for delta virus: Is a cure in sight?

Current treatment of chronic hepatitis D viral infection with interferons is poorly tolerated and effective only in a minority of patients. Despite delta virus causing the most severe form of chronic viral hepatitis, no other treatments are available. After many years of inactivity, there is now hope for new treatment approaches for delta virus and some are likely to enter clinical practice in the near future. Four new treatment approaches are currently being evaluated in phase 2 studies. These involve the hepatocyte entry inhibitor myrcludex B, the farnesyl transferase inhibitor lonafarnib, the nucleic acid inhibitor REP 2139 Ca and pegylated interferon lambda. Results obtained so far are promising, and phase 3 studies are expected shortly. This review summarizes the available data on the efficacy and safety of these new drugs.

Aiming towards hepatitis C virus elimination in Greece.

There are estimated to be 74,000-134,000 patients living with chronic hepatitis C in Greece, but only 20-30% of them are aware of their disease status. In July 2017, the Hellenic National Plan for Hepatitis C was announced in alignment with the World Health Organization goals for the eradication of hepatitis C virus (HCV) by the year 2030. This article discusses the epidemiology and current treatment of chronic hepatitis C in Greece. Additionally the authors propose actions on how to bring back to care diagnosed patients lost to follow up, optimize access to care for HCV-infected people who inject drugs, and increase HCV screening in the general population. The medical community in Greece can play a pivotal role in the implementation of the HCV National Plan and in the efforts to reach the goal of HCV elimination.

Tenofovir and entecavir for chronic hepatitis B infection treatment: a single-center experience

BACKGROUND AND AIM: The current treatment of chronic hepatitis B infection (CHBV) has achieved several step-ups thanks to the introduction of the new-generation nucleos(t)ide analogs. Entecavir and tenofovir have shown a high genetic resistance barrier and a low rate of side effects. In literature, there are a few studies comparing entecavir and tenofovir in the treatment of CHBV. Thus, we describe the results of our experience in managing CHBV patients with tenofovir vs. entecavir.MATERIALS AND METHODS: We have retrospectively evaluated, from 2007 to date, 20 CHBV patients treated with entecavir and tenofovir. All the patients underwent basal and periodical clinical follow-up, blood tests, virological tests, Fibroscan® test or liver biopsy and also upper abdominal ultrasound examination. Study endpoints were: viral replication inhibition, viral antigens seroconversion and transaminases normalization. Drug-associated side effects were also registered.RESULTS: After 12 weeks of therapy, entecavir and tenofovir lead to HBV-DNA negativization in 44% and 62% of patients, respectively. A case of viral seroconversion for HBeAg and HBsAg was evident in entecavir group, while no cases were registered in tenofovir group. After 12 weeks, 11% of entecavir treated patients and 37% of tenofovir treated patients showed normalization of transaminases.DISCUSSION: Tenofovir seems to exert a better viral replication inhibition (though not statistically significant) and to show transaminases improvement in comparison with entecavir, which, in turn, results more effective in HBeAg/HBsAg seroconversion. Both drugs have a high safety profile in terms of side effects.[Article in Italian]

In vivo reduction of hepatitis B virus antigenemia and viremia by antisense oligonucleotides

Current treatment of chronic hepatitis B virus infection (CHB) includes interferon and nucleos(t)ide analogues, which generally do not reduce HBV surface antigen (HBsAg) production, a constellation that is associated with poor prognosis of CHB. Here we evaluated the efficacy of an antisense approach using antisense oligonucleotide (ASO) technology already in clinical use for liver targeted therapy to specifically inhibit HBsAg production and viremia in a preclinical setting. A lead ASO was identified and characterized in vitro and subsequently tested for efficacy in vivo and in vitro using HBV transgenic and hydrodynamic transfection mouse and a cell culture HBV infection model, respectively. ASO treatment decreased serum HBsAg levels ⩾2 logs in a dose and time-dependent manner; HBsAg decreased 2 logs in a week and returned to baseline 4 weeks after a single ASO injection. ASO treatment effectively reduced HBsAg in combination with entecavir, while the nucleoside analogue alone did not. ASO treatment has pan-genotypic antiviral activity in the hydrodynamic transfection system. Finally, cccDNA-driven HBV gene expression is ASO sensitive in HBV infected cells in vitro. Our results demonstrate in a preclinical setting the efficacy of an antisense approach against HBV by efficiently reducing serum HBsAg (as well as viremia) across different genotypes alone or in combination with standard nucleoside therapy. Since the applied antisense technology is already in clinical use, a lead compound can be rapidly validated in a clinical setting and thus, constitutes a novel therapeutic approach targeting chronic HBV infection.

Chronic Hepatitis C Treatment in a Thalassemia Major Patient: A Case Report

OZET Thalassemia major patients with chronic hepatitis C have increased risk for developing fibrosis and hepatocellular carcinoma due to liver damage caused by these two diseases. Although the current treatment of chronic hepatitis is based on binary combinations, the use of ribavirin in combination with peginterferon alfa2a or b in patients with hemoglobinopathies is not recommended by the treatment guidelines. However, it is observed that there have been changes in the applications presented in the guidelines over the years. This paper presents the outcomes and side effects of treatment given to thalassemia major patients with chronic hepatitis C. (Viral Hepatitis Journal 2014; 20(3): 134-137)

Pulmonary manifestations associated with the current treatment of chronic hepatitis C

resUmO A hepatite C e dos principais problemas mundiais de saude publica da atualidade, com prevalencia global media proxima de 3%. A maioria dos infectados (70%) desenvolve hepatite cronica e cirrose hepatica. Atualmente, dois agentes, o interferon peguilado (PEG-INF) e a ribavirina, tem sido empregados no tratamento da hepatite C cronica. Os efeitos colaterais e eventos adversos atribuidos ao tratamento da hepatite C cronica com interferons peguilados e ribavirina vem sendo mais bem reconhecidos na atualidade. Alteracoes pulmonares tem sido descritas durante o uso dessas drogas e variam com manifestacoes desde leves a potencialmente graves. Considerando o uso cada vez mais frequente do interferon na hepatite C e em outras doencas, esta revisao objetiva auxiliar no pronto reconhecimento dos efeitos colaterais pulmonares dessa droga, assim como o seu adequado manejo. Palavras-chave: Hepatite C; Hepatite C/terapia; Pneumopatias; Interferons/efeitos adversos; Ribavirina/efeitos adversos.

Ezetimibe blocks hepatitis B virus infection after virus uptake into hepatocytes

Current treatment of chronic hepatitis B virus (HBV) infection mainly targets viral replication in hepatocytes and leads to curing only in exceptional cases. Despite their potential to improve therapeutic success, no drugs interfering with early infection steps of the hepatotropic pathogen HBV are available to date. Recently, entry of the hepatitis C virus (HCV) has been shown to occur along hepatic cholesterol uptake pathways and ezetimibe, a drug which blocks this lipid transport, has been shown to inhibit HCV infection. We here investigated the effect of ezetimibe on HBV infection using differentiated HepaRG cells as a cell-culture infection model. Treatment with ezetimibe inhibited establishment of intrahepatic cccDNA and expression of viral replication markers when cells were infected with HBV virions, while we observed no effect when the HBV viral genome was transduced via an adenoviral vector. Our data suggest that modulating hepatic cholesterol uptake by ezetimibe inhibits early HBV infection and that ezetimibe sensitive lipid transport pathways represent new targets for antiviral therapy in HBV infection.

Traitements personnalisés du virus de l’hépatite C

The current treatment of chronic hepatitis C since several years, the association of pegylated interferon and ribavirine, allows to obtain a virological eradication in around 55% of patients, including 45% of those infected with the genotype 1. The cure, defined by an undetectable viremia 24 weeks after the discontinuation of treatment, is associated to an improvement of the prognosis of the patients with a decrease of mortality and morbidity. If the virologic recovery allows fibrosis regression, including cirrhosis reversal, why not to treat every HCV-infected patient? Because first therapy is not mandatory in all the patients (minim liver disease, co-morbidities which may be contraindications to therapy), second adverse events are frequent and may be severe, third costs are high (the antiviral treatment but also hematological growth factors…) and finally the treated patients do not recover constantly. This has resulted in personalized therapies based on the severity of the disease, the early viral kinetics, pharmacologic monitoring, genetic and immunological factors. In addition to these factors of personalization, the development of new anti-viral C molecules, the protease inhibitors (boceprevir or telaprevir which are about to be approved in combination with pegylated interferon and ribavirine) will allow to achieve a sustained virologic response in around 75% of cases.

Management of side-effects

The current treatment of chronic hepatitis C is the triple combination of pegylated interferon, ribavirin and a new direct-acting antiviral [either telaprevir (TVR) or boceprevir (BOC)]. This new association produces better viral response rates, but may induce or enhance adverse events, which can lead to discontinuation of treatment. TVR regimens are associated with an increased risk of dermatological side-effects such as rash, albeit generally mild. In these cases, optimal skincare treatments, including emollient creams and topical corticosteroids, allow the continuation of antiviral treatment. In a minority of cases, the rash may be severe and life-threatening, leading to immediate discontinuation of all treatments. The goal for the physician is to differentiate severe cutaneous adverse reactions (SCARs), including DRESS (drug reactions with eosinophilia and systemic symptoms). Anaemia is also more frequent with triple combinations using TVR or BOC. The management of anaemia requires the use of erythropoietin alpha (EPO) and the need to decrease ribavirin doses. Thus, monitoring haemoglobin has to be more frequent in difficult-to-treat patients such as cirrhosis cases; nevertheless, despite the use of EPO and ribavirin-dose adaptation, blood transfusion is sometimes still required. Thus, triple combination therapy with a DAA is effective, but it increases the rate of adverse events, and adds to the well-known adverse effects of pegylated interferon and ribavirin. This suggests the need for a different clinical and biological management of patients treated with the triple combination.

The Treatment Response of Chronically Hepatitis C Virus-Infected Patients Depends on Interferon Concentration but Not on Interferon Gene Expression in Peripheral Blood Mononuclear Cells

The current treatment of chronic hepatitis C is based on pegylated alpha interferon (PEG-IFN-α) and ribavirin. The aim of this study was to identify biological and clinical variables related to IFN therapy that could predict patient outcome. The study enrolled 47 patients treated with PEG-IFN and ribavirin combined therapy. The interferon concentration was measured in serum by a bioassay. The expression of 93 interferon-regulated genes in peripheral blood mononuclear cells was quantified by real-time quantitative reverse transcription-PCR (RT-PCR) before and after 1 month of treatment. The interferon concentration in the serum was significantly lower in nonresponders than in sustained virological responders. Moreover, a significant correlation was identified between interferon concentration and interferon exposition as well as body weight. The analysis of interferon-inducible genes in peripheral blood mononuclear cells among the genes tested did not permit the prediction of treatment outcome. In conclusion, the better option seems to be to treat patients with weight-adjusted PEG-IFN doses, particularly for patients with high weight who are treated with PEG-IFN-α2a. Although the peripheral blood mononuclear cell samples are the easiest to obtain, the measurement of interferon-inducible genes seems not be the best strategy to predict treatment outcome.

Nuevos agentes para el tratamiento de la hepatitis C

The current treatment of Chronic Hepatitis C (CHC) is based on the combination of peginterferon alpha 2a or 2b and ribavirin. This treatment achieves Sustained Virological Response (SVR) rates in more than 50% of the patients. The SVR rates are higher in genotype 2 and 3 patients than in genotype 1, which account for more than 50%. For this reason, the development of new drugs is needed. The knowledge of Hepatitis C Virus (HCV) replication cycle and the characterisation of the viral enzymes allow targets to be defined with the ability to inhibit HCV enzymes. The present overview analyses the first two NS3/NS4 protease inhibitors approved for the treatment of CHC, boceprevir and telaprevir. Both increase rates of SVR in naïve and in previously treated patients with the advantage that in some cases therapy can be shortened. However, these drugs have new side effects such as a rash and an increase in the rate of anaemia.

Nouveaux traitements de l’hépatite C chronique

The current treatment of chronic hepatitis C since several years, the association of pegylated interferon and ribavirine, allows to obtain a virological eradication in 55% of patients, all genotypes and 45% of those infected with the genotype 1, the most prevalent. The cure, defined by an undetectable viremia 24 weeks after the discontinuation of treatment is associated to a improvement of the prognosis of the patients with a decrease of mortality and morbidity. The development of news antiviral C molecules, efficient against the genotype 1, two protease inhibitors, boceprevir or telaprevir (which approval has been recently obtained), in association with pegylated interferon and ribavirine, allows to obtain a viral eradication in 70 to 75% of cases, with a reduction of treatment duration to 24 weeks in half of patients. This evolution will modify the therapeutic indications, the therapeutic schemas, the virologic follow-up, the risk factors of sustained virological reponse, the tolerance with the appearance of new adverse effects.

Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus

Current treatment of chronic hepatitis C virus (HCV) infection is based on the combination of pegylated interferon-α and ribavirin. The recent development of direct-acting antiviral (DAA) molecules that are active on HCV, together with in vitro and in vivo studies showing that these drugs may lead to the selection of resistant viruses if administered alone, has raised concerns that resistance may undermine therapy based on DAAs. A new standard-of-care treatment will soon be available for both treatment-naive and treatment-experienced patients infected with HCV genotype 1, based on a triple combination of pegylated interferon-α, ribavirin, and a protease inhibitor (either telaprevir or boceprevir). With this therapy, most failures to eradicate infection in treatment-adherent patients are due to an inadequate response to pegylated interferon-α and ribavirin, in the context of a low genetic barrier to resistance of first-generation protease inhibitors. This article reviews patterns of resistance to HCV DAA drugs in development, the mechanisms underlying treatment failure when these drugs are combined with pegylated interferon-α and ribavirin, the consequences of treatment failure, and possible means of optimizing future therapies that use DAAs.

Baseline Prediction of Combination Therapy Outcome in Hepatitis C Virus 1b Infected Patients by Discriminant Analysis Using Viral and Host Factors

BackgroundCurrent treatment of chronic hepatitis C virus (HCV) infection has limited efficacy −especially among genotype 1 infected patients−, is costly, and involves severe side effects. Thus, predicting non-response is of major interest for both patient wellbeing and health care expense. At present, treatment cannot be individualized on the basis of any baseline predictor of response. We aimed to identify pre-treatment clinical and virological parameters associated with treatment failure, as well as to assess whether therapy outcome could be predicted at baseline.MethodologyForty-three HCV subtype 1b (HCV-1b) chronically infected patients treated with pegylated-interferon alpha plus ribavirin were retrospectively studied (21 responders and 22 non-responders). Host (gender, age, weight, transaminase levels, fibrosis stage, and source of infection) and viral-related factors (viral load, and genetic variability in the E1–E2 and Core regions) were assessed. Logistic regression and discriminant analyses were used to develop predictive models. A “leave-one-out” cross-validation method was used to assess the reliability of the discriminant models.Principal FindingsLower alanine transaminase levels (ALT, p = 0.009), a higher number of quasispecies variants in the E1–E2 region (number of haplotypes, nHap_E1–E2) (p = 0.003), and the absence of both amino acid arginine at position 70 and leucine at position 91 in the Core region (p = 0.039) were significantly associated with treatment failure. Therapy outcome was most accurately predicted by discriminant analysis (90.5% sensitivity and 95.5% specificity, 85.7% sensitivity and 81.8% specificity after cross-validation); the most significant variables included in the predictive model were the Core amino acid pattern, the nHap_E1–E2, and gamma-glutamyl transferase and ALT levels.Conclusions and SignificanceDiscriminant analysis has been shown as a useful tool to predict treatment outcome using baseline HCV genetic variability and host characteristics. The discriminant models obtained in this study led to accurate predictions in our population of Spanish HCV-1b treatment naïve patients.

Retreatment of Patients Nonresponsive to Pegylated Interferon and Ribavirin with Daily High-Dose Consensus Interferon

Background. Current treatment of chronic hepatitis C with pegylated interferon and ribavirin has the ability to eliminate viral infection in about half of the patients treated. Therapeutic options, for those with remaining chronic hepatitis, will remain limited until novel antivirals become available in the future. Consensus interferon is currently available and has demonstrated clinical efficacy with superior invitro antiviral activity, but the maximum tolerated dose is not defined. Methods. We assessed the efficacy of daily high-dose (24 ug) consensus interferon with weight-based (1000–1200 mg daily) ribavirin in HCV genotype 1-infected non-responder patients. Results. Six adverse events were documented in five patients, and the trial was terminated with no subject achieving viral clearance. Conclusions. The occurrence of serious adverse events effectively defined the upper limit of acceptable dose, while also revealing that this dose did not offer enhanced sustained viral clearance.

Preclinical and Clinical Development of Pegylated Interferon-Lambda 1 in Chronic Hepatitis C

Current treatment of chronic hepatitis C consists of pegylated interferon-alpha (PEG-IFN-alpha) in combination with ribavirin. This regimen is associated with adverse effects that can limit its use. PEG-IFN-lambda 1 (pegIFNlambda) is a novel IFN that shares many of the biological effects of IFN-alpha but may have fewer side effects due to its more selective receptor distribution. Preclinical data show that pegIFNlambda has antiviral activity against hepatitis C virus (HCV) but does not inhibit myeloid colony formation. A phase 1 study in healthy volunteers demonstrated that pegIFNlambda is well tolerated. Elevated liver enzymes resulted in a dose-limiting toxicity after a single dose of 7.5 microg/kg, the highest dose tested. A phase 1b study in genotype 1 HCV patients who either relapsed after IFN-alpha therapy or naive to therapy was initiated. Interim data from the treatment relapse subset showed viral load reductions of 2.3 to 4.0 logs when pegIFNlambda was administered weekly as a single agent with or without ribavirin for up to 4 weeks. Drug-related side effects included elevation of liver enzymes. Decreases in hemoglobin were observed only in patients receiving ribavirin. Constitutional symptoms appeared lower than historical data for PEG-IFN-alpha. These results form the basis of further development of pegIFNlambda as a novel treatment for chronic hepatitis C.

Development of novel therapeutics for chronic hepatitis B

Chronic infection of hepatitis B virus (HBV) presents one of the serious public health challenges worldwide. Current treatment of chronic hepatitis B (CHB) is limited, and is composed of interferon and nucleoside/nucleotide reverse transcriptase inhibitors (NRTI). Interferon is poorly tolerated and is only responsive in a small fraction of CHB patients and NRTIs often face the problem of emergence of drug resistance during long-term treatment. The current treatment of CHB can be improved in several ways including genotyping mutations associated with drug resistance before treatment to guide the choice of NRTIs and suitable combinations among NRTIs and interferon. It is important to continue research in the identification of novel therapeutic targets in the life cycle of HBV or in the host immune system to stimulate the development of new antiviral agents and immunotherapies. Several antiviral agents targeting HBV entry, cccDNA, capsid formation, viral morphogenesis and virion secretion, as well as two therapeutic vaccines are currently being evaluated in preclinical studies or in clinical trials to assess their anti-HBV efficacy.