Drug-induced liver injury (DILI) and herb-induced liver injury (HILI) are typical diseases of clinical and translational hepatology. Their diagnosis is complex and requires an experienced clinician to translate basic science into clinical judgment and identify a valid causality algorithm. To prospectively assess causality starting on the day DILI or HILI is suspected, the best approach for physicians is to use the Council for International Organizations of Medical Sciences (CIOMS) scale in its original or preferably its updated version. The CIOMS scale is validated, liver-specific, structured, and quantitative, providing final causality grades based on scores of specific items for individual patients. These items include latency period, decline in liver values after treatment cessation, risk factors, co-medication, alternative diagnoses, hepatotoxicity track record of the suspected product, and unintentional re-exposure. Provided causality is established as probable or highly probable, data of the CIOMS scale with all individual items, a short clinical report, and complete raw data should be transmitted to the regulatory agencies, manufacturers, expert panels, and possibly to the scientific community for further refinement of the causality evaluation in a setting of retrospective expert opinion. Good-quality case data combined with thorough CIOMS-based assessment as a standardized approach should avert subsequent necessity for other complex causality assessment methods that may have inter-rater problems because of poor-quality data. In the future, the CIOMS scale will continue to be the preferred tool to assess causality of DILI and HILI cases and should be used consistently, both prospectively by physicians, and retrospectively for subsequent expert opinion if needed. For comparability and international harmonization, all parties assessing causality in DILI and HILI cases should attempt this standardized approach using the updated CIOMS scale.

Exploration of naturally occurring chemical structures for medicinal uses has received significant interest in drug discovery and development research in the past few decades. None have had more success or products of greater clinical efficacy than synthetic analogs of nucleosides and nucleotides, especially as antiviral drugs. Nucleos(t)ide antivirals are synthetic analogs of the natural building blocks of DNA or RNA. This review focuses on the developmental path of tenofovir disoproxil fumarate (TDF), a prodrug of a nucleotide analog and its clinical applications as a first-line antiviral for chronic hepatitis B (CHB).

Tenofovir is a potent antiviral compound, but has poor oral availability. The disoproxil fumarate (DF) prodrug moiety greatly enhances intestinal absorption allowing it to become an oral medication. Tenofovir is activated intracellularly, and the incorporation into HBV DNA prevents further elongation thus terminating replication. In patients with CHB, TDF has demonstrated broad, potent and sustained virologic response. Maintenance of viral suppression for up to 5 years resulted in regression of fibrosis and cirrhosis. No tenofovir-resistant HBV variants have been detected in patients after long-term use. The efficacy and safety profiles reported from cohort studies of clinical practices were consistent with those observed in registration trials.

Continuous development includes a new oral prodrug, tenofovir alafenamide fumarate (TAF), which has enhanced delivery of tenofovir to target cells compared to TDF.

In a recent genome-wide association study, single nucleotide polymorphisms (SNPs) located near the interleukin-28B gene (IL28B), which encodes type III interferon (IFN) λ3, were shown to be strongly associated with a viral response to pegylated IFNα (PEG-IFNα) and ribavirin (RBV) combination therapy and spontaneous viral clearance in patients chronically and acutely infected with hepatitis C virus (HCV), respectively. The global distribution of allele frequencies shows a remarkable pattern, in which a favorable allele is nearly fixed in East Asia, has an intermediate frequency in Europe, and is least frequent in Africa. Although the underlying mechanisms responsible for viral responses associated with IL28B SNPs have not been completely elucidated, IFN-stimulated gene expression in patients with unfavorable IL28B genotypes tends to be high at baseline and is insufficiently induced by exogenous IFN administration, resulting in poor treatment outcomes. Clinically, triple therapy with PEG-IFNα/RBV together with direct-acting antiviral agents (DAAs) is currently used to treat chronic hepatitis C as a first-line therapy. Although the predictive power of IL28B status may be attenuated, the IL28B genotype will remain relevant to the outcomes of DAA therapy when used in combination with PEG-IFNα as a backbone. Even with the introduction of IFN-free therapies with a new class of highly effective DAAs, IL28B SNPs are still useful predictors of treatment outcomes and can be used to individualize treatment strategies to maximize cost-effectiveness and identify patients at risk of being refractory to treatment. This review summarizes the current understanding of the clinical significance and role of IL28B in HCV infection and response to therapy.

Hepatitis C virus (HCV) infects nearly 170 million people worldwide and causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The search for a drug regimen that maximizes efficacy and minimizes side effects is quickly evolving. This review will discuss a wide range of drug targets currently in all phases of development for the treatment of HCV. Direct data from agents in phase III/IV clinical trials will be presented, along with reported side-effect profiles. The mechanism of action of all treatments and resistance issues are highlighted. Special attention is given to available trial data supporting interferon-free treatment regimens. HCV has become an increasingly important public health concern, and it is important for physicians to stay up to date on the rapidly growing novel therapeutic options.

An estimated 2–3% of the world's population is infected with hepatitis C virus (HCV), making it a major global health problem. Consequently, over the past 15 years, there has been a concerted effort to understand the pathophysiology of HCV infection and the molecular virology of replication, and to utilize this knowledge for the development of more effective treatments. The virally encoded non-structural serine protease (NS3) is required to process the HCV polyprotein and release the individual proteins that form the viral RNA replication machinery. Given its critical role in the replication of HCV, the NS3 protease has been recognized as a potential drug target for the development of selective HCV therapies. In this review, we describe the key scientific discoveries that led to the approval of boceprevir, a first-generation, selective, small molecule inhibitor of the NS3 protease. We highlight the early studies that reported the crystal structure of the NS3 protease, its role in the processing of the HCV polyprotein, and the structural requirements critical for substrate cleavage. We also consider the novel attributes of the NS3 protease-binding pocket that challenged development of small molecule inhibitors, and the studies that ultimately yielded milligram quantities of this enzyme in a soluble, tractable form suitable for inhibitor screening programs. Finally, we describe the discovery of boceprevir, from the early chemistry studies, through the development of high-throughput assays, to the phase III clinical development program that ultimately provided the basis for approval of this drug. This latest phase in the development of boceprevir represents the culmination of a major global effort to understand the pathophysiology of HCV and develop small molecule inhibitors for the NS3 protease.

A number of disease-associated genetic markers for common liver diseases have been identified using genome-wide association studies (GWASs). The GWAS strategy is based on genome-wide single-nucleotide polymorphism typing technologies, which are now commercially available, accompanied by statistical methods to identify host genetic factors that are associated with target diseases or complex genetic traits. One of the most striking features of the GWAS strategy is the ability to identify unexpected disease-associated genetic markers across the entire human genome. Here, we describe the technological aspects of the GWAS strategy with examples from actual GWAS reports related to hepatitis research, including drug response for patients with chronic hepatitis C, susceptibility to primary biliary cirrhosis, and hepatitis-B-related hepatocellular carcinoma.

Since the first approval of interferon for the treatment of chronic hepatitis B virus (HBV) infection in 1992, six additional antivirals have been developed: pegylated interferon-alfa2a, and the oral antivirals lamivudine, adefovir, telbivudine, entecavir and tenofovir. The availability of animal models for HBV infection and hepatocyte cell culture led to the discovery and development of oral antivirals targeted at HBV polymerase and reverse transcriptase, which inhibit viral replication. The discovery and development of entecavir, the first oral anti-HBV drug with both potent antiviral activity and a high genetic barrier to resistance, took more than 10 years before it was first approved in the USA. Since then, multiple real-life studies have provided data consistent with the findings of the registration trials and the long-term rollover study in terms of efficacy, resistance, and safety. Data from the long-term follow-up of patients enrolled in the registration studies showed that treatment with entecavir can lead to significant improvements in liver histopathology, and recent cohort studies have demonstrated that treatment with entecavir may reduce disease progression and the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. In addition, real-life studies suggest that entecavir may reduce HCC recurrence and increase survival rates in patients with HBV-related HCC post-surgical resection.