Residual HBV DNA and pgRNA viraemia is associated with hepatocellular carcinoma in chronic hepatitis B patients on antiviral therapy

Journal of Gastroenterology - We aimed to assess whether residual hepatitis B virus (HBV) viraemia is associated with HCC development. This is a case–control study of 104 patients [52 HCC and...     

Pharmacokinetic evaluation of besifovir for the treatment of HBV infection

Introduction: Besifovir (LB80380) is a relatively new oral acyclic nucleotide phosphonate. We reviewed the pharmacokinetic characteristics of LB80380 and discussed its role in the treatment of chronic hepatitis B infection.

Areas covered: LB80380 is a prodrug of LB80331 and LB80317. It is rapidly absorbed when taken orally. Escalating doses of besifovir produce linear increase of the plasma concentration. Doses above 60mg are effective for inhibiting HBV in human. Using 60mg as an example, the maximal concentration of LB80331 in plasma is 397 ng/mL. The time required to reach maximal concentration in plasma and elimination half-life are 2.0 and 3.0 h, respectively. Besifovir and its metabolites are mainly excreted via the kidneys. Its antiviral efficacy is non-inferior to ETV 0.5mg daily. It is generally safe in terms of renal and bone toxicity. The most common adverse event is carnitine depletion which affects almost all patients on besifovir requiring carnitine supplementation.

Expert opinion: Besifovir demonstrated predictable pharmacokinetic characteristics in human subjects. Few clinical studies on besifovir have been conducted. More data are expected particularly for special populations. The adverse events upon long term exposure should be monitored. Large scale head-to-head trials comparing besifovir with existing NA, especially tenofovir alafenamide, should be conducted.     

An update on the toxicological considerations for protease inhibitors used for hepatitis C infection

Introduction: Hepatitis C virus protease inhibitors (PIs) are important components of many direct acting antiviral regimens. Many clinical trials and real-world studies have described the safety data for individual PIs. We aimed to review the safety of both the first and second generation PIs in patients with chronic hepatitis C (CHC).

Areas covered: The unique pharmacokinetic properties of PIs partly explain their toxicities. Second generation PIs, when used without interferon and ribavirin, are well-tolerated. Use of PIs in renal impaired patients or those on dialysis appears to be safe. Decompensated cirrhosis is a contraindication for PIs use due to increased drug exposure and risk of liver decompensation. Drug-drug interactions are common and should be always monitored; some drugs should not be co-administered with PIs. In patients with co-infected hepatitis B virus, reactivation after DAA (whether PI-containing or not) is a concern.

Expert opinion: Second generation PIs are key players in the current DAA era. Post-marketing surveillance is essential to monitor unknown adverse events and drug–drug interactions. Non-PI based DAA should be used in decompensated liver disease. The use of these drugs should also be explored in the paediatric population.     

Carbon monoxide inhibits apoptosis during cold storage and protects kidney grafts donated after cardiac death

Ischemia/reperfusion (I/R) injury remains as a serious deleterious factor in kidney transplantation (KTx). We hypothesized that carbon monoxide (CO), an endogenous potent cytoprotective molecule, inhibits hypothermia-induced apoptosis of kidney grafts. Using the rat KTx model mimicking the conditions of donation after cardiac death (DCD) as well as nontransplantable human kidney grafts, this study examined effects of CO in preservation solution in improving the quality of marginal kidney grafts. After cardiac cessation, rat kidneys underwent 40 min warm ischemia (WI) and 24 h cold storage (CS) in control UW or UW containing CO (CO-UW). At the end of CS, kidney grafts in control UW markedly increased mitochondrial porin release into the cytosol and resulted in increased cleaved caspase-3 and PARP expression. In contrast, grafts in CO-UW had significantly reduced mitochondrial breakdown and caspase pathway activation. After KTx, recipient survival significantly improved with CO-UW with less TUNEL(+) cells and reduced mRNA upregulation for proinflammatory mediators (IL-6, TNF-α, iNOS). Furthermore, when nontransplantable human kidney grafts were stored in CO-UW for 24 h, graft PARP expression, TUNEL(+) cells, and proinflammatory mediators were less than those in control UW. CO in UW inhibited hypothermia-induced apoptosis and significantly improved kidney graft function and outcomes of KTx.     

Hepatitis delta virus: Disease assessment and stratification

Hepatitis D virus (HDV) causes one of the most severe forms of hepatitis in people with chronic hepatitis B (CHB) infection. Timely and accurate assessment of hepatitis delta virus (HDV) and disease stratification is mandatory for thorough pre-therapeutic evaluation for prioritizing treatment and outcome prediction. Viral biomarkers associated with HDV and hepatitis B virus (HBV) are crucial to aid in diagnosis, and monitoring of serum viral nucleic acids for both viruses is recommended. Liver biopsy remains the gold standard for staging of liver fibrosis and grading of histological activity and should remain central for diagnostic purposes, but is also of importance for research to enhance our understanding of HDV. The emergence of novel non-invasive tests for the assessment of liver fibrosis in HDV patients coupled with the well-recognized potential complications of liver biopsy has resulted in reduced utility of liver biopsy in clinical practice. Preliminary data suggest that these emerging non-invasive modalities appear to be reliable, and their use is supported, similar to other viral hepatitis. Nevertheless, further validation is required before their widespread adoption into clinical practice.     

Novel developments of hepatitis B: treatment goals,agents and monitoring tools

Introduction: Chronic hepatitis B (CHB) infection causes considerable morbidity and mortality and hence should be a target for global elimination. In recent years, advances have been made in understanding the disease pathophysiology and the relationship to clinical outcome. Novel treatment targets are actively being sought in the hope of improving the treatment outlook.

Areas covered: We discussed the cascade of cure of CHB with respect to the degree of persistence of viral genome and proteins. Several novel antiviral agents either targeting the virus or the host are in different clinical phases of development. Serum hepatitis B core-related antigen and HBV RNA are novel markers, which might have a role in the prediction of specific clinical outcomes such as development of hepatocellular carcinoma or virological relapse after cessation of antiviral therapy. These markers may also be used to monitor treatment response in the drug trials.

Expert commentary: Global elimination of CHB is challenged by extremely low awareness of illness and poor access to care. CHB and its related complications can be reduced by birth dose vaccine, antiviral therapy, and alleviated by complication screening. Treatment options for CHB will expand in the next decade and early functional cure is not an impractical goal.