Chronic hepatitis B (CHB) remains a major global public health problem. The functional cure is the ideal therapeutic target recommended by the latest guidelines, and pursuing a functional cure has become the key treatment end point of current therapy and for upcoming clinical trials. In this review, based on the latest published clinical research evidence, we analyzed the concept and connotation of clinical cures and elaborated on the benefits of clinical cures in detail. Secondly, we have summarized various potential treatment methods for achieving clinical cures, especially elaborating on the latest research progress of interferon-based optimized treatment strategies in achieving clinical cures. We also analyzed which populations can achieve clinical cures and conducted a detailed analysis of relevant virological and serological markers in screening clinical cure advantage populations and predicting clinical cure achievement. In addition, we also introduced the difficulties that may be encountered in the current pursuit of achieving a clinical cure.

Chronic hepatitis B virus (HBV) infection is a global public health challenge since more than 250 million individuals are affected worldwide. Since different treatment modalities are available and not all patients are candidates for antiviral treatment, biomarkers that potentially predict the possibility of HBsAg clearance and seroconversion may be useful in clinical practice.

In this retrospective study, we aimed to identify factors positively correlated with HBsAg seroconversion in a large cohort of 371 chronic hepatitis B patients treated at a German tertial center between 2005 and 2020.

Seroconversion occurred in 25/371 (6.7%) and HBsAg loss in 29/371 patients (7.8%) with chronic HBV infection. Antiviral therapy was associated with a lower chance of seroconversion (seroconversion antiviral therapy 14/260 (5.4%) vs. therapy-naïve patients 11/111 (9.9%), p = 0.027). Seroconversion rates were higher in patients with (very) low titers of HBV DNA (best cut-off value 357 IU/mL) and quantitative HBsAg. The best cut-off value with regard to seroconversion was 357 IU/mL for HBV DNA (AUC 0.693 (95%-CI 0.063-0.422), sensitivity 0.714, specificity 0.729; p < 0.0005) and 33,55 IU/mL for HBsAg (AUC 0.794 (95%-CI 0.651-0.937), sensitivity 0.714, specificity 0.949; p < 0.0005). However, male gender was positively associated with seroconversion (seroconversion: males 7.6% vs. females 2.7%, p = 0.036).

Treatment-naïve male chronic HBV patients with low viral load and inflammatory activity have the best chance to achieve seroconversion. In the absence of cirrhosis, antiviral therapy should therefore not be performed in this patient collective.

Asthma is a chronic respiratory disease affecting people of all ages, especially children, worldwide. Origins of asthma are suggested to be placed in early life with heterogeneous clinical presentation, severity and pathophysiology. Exacerbations of asthma disease can be triggered by many factors, including viral respiratory tract infections. Rhinovirus (RV) induced respiratory infections are the predominant cause of the common cold and also play a crucial role in asthma development and exacerbations. Rhinovirus mainly replicates in epithelial cells lining the upper and lower respiratory tract. Type III interferons, also known as interferon-lambda (IFNλ), are potent immune mediators of resolution of infectious diseases but they are known to be involved in autoimmune diseases as well. The protective role of type III IFNs in antiviral, antibacterial, antifungal and antiprotozoal functions is of major importance for our innate immune system. The IFNλ receptor (IFNλR) is expressed in selected types of cells like epithelial cells, thus orchestrating a specific immune response at the site of viruses and bacteria entry into the body. In asthma, IFNλ restricts the development of TH2 cells, which are induced in the airways of asthmatic patients. Several studies described type III IFNs as the predominant type of interferon increased after infection caused by respiratory viruses. It efficiently reduces viral replication, viral spread into the lungs and viral transmission from infected to naive individuals. Several reports showed that bronchial epithelial cells from asthmatic subjects have a deficient response of type III interferon after RV infection ex vivo. Toll like Receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) expressed on infectious agents, and induce the development of antiviral and antibacterial immunity. We recently discovered that activation of TLR7/8 resulted in enhanced IFNλ receptor mRNA expression in PBMCs of healthy and asthmatic children, opening new therapeutic frontiers for rhinovirus-induced asthma. This article reviews the recent advances of the literature on the regulated expression of type III Interferons and their receptor in association with rhinovirus infection in asthmatic subjects.

BACKGROUND High rates of HBeAg and/or HBsAg seroconversion or clearance have been achieved in chronic hepatitis B (CHB) patients receiving pegylated interferon (pegIFN) in addition to ongoing nucleos(t)ide analogue (NUC) treatment. In the present study, we aimed to evaluate HBsAg kinetics to predict HBeAg seroconversion and HBsAg clearance in these patients. MATERIAL AND METHODS A total of 33 HBeAg-positive and 17 HBeAg-negative patients were enrolled between January 2010 and January 2018. At the end of pegIFN treatment, 9 of 50 patients achieved HBsAg clearance, and 9 of 33 HBeAg-positive patients achieved HBeAg seroconversion. RESULTS The cutoff value of 0.41 log₁₀ IU/mL in HBsAg decline at week 12 had a positive predictive value (PPV) of 58.3% and a negative predictive value (NPV) of 94.6% for HBsAg clearance. The cutoff value of 1.94 log₁₀ IU/mL in HBsAg decline at week 24 had a PPV of 80.0% and an NPV of 97.5% for HBsAg clearance. The cutoff value of 0.47 log₁₀ IU/mL in HBsAg decline at week 12 had a PPV of 83.3% and an NPV of 85.2% for HBeAg seroconversion. The cutoff value of 1.29 log₁₀ IU/mL in in HBsAg decline at week 24 had a PPV of 85.7% and an NPV of 88.5% for HBeAg seroconversion. CONCLUSIONS Early HBsAg drop has a high predictive value for HBsAg clearance and HBeAg seroconversion in patients who were treated with combination therapy of pegIFN and NUCs.

Chronic hepatitis B (CHB) is currently medically managed with either interferon-alpha or one of the five nucleos(t)ide analogs. However, there are still a large number of CHB patients whose response to the above therapies remains less than satisfactory, and their incomplete or non-response to antiviral therapies has plagued clinicians worldwide. In recent years, a newly proposed optimization therapy has provided us with a new approach to solve this problem. The key points in this optimization therapy are to initiate antiviral therapy with an appropriate agent at the correct time point, and to adjust treatments in patients with poor early responses by adding a second agent or switching to another more potent agent. In this review, we summarize recent developments in optimization therapy for the treatment of CHB, and provide an outlook for future research in this field.