Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients.

Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.

Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States.

Hyperprogression in hepatocellular carcinoma: Illusion or reality?

Hepatocellular carcinoma (HCC) is a prevalent liver cancer associated with global health. The tumor microenvironment's (TME) microbial composition significantly influences HCC's development and prognosis. This study analyzed bacterial 16S rRNA genes from liver cancer patients' tumor, adjacent tumor, and normal tissues, revealing distinct microbiome profiles between tumor and normal tissues. HCC microbiota was more abundant, with Bacteroides, Ochrobactrum, Akkermansia, and Lactobacillus as the most prevalent genera. Hepatitis B virus (HBV)-positive (HBV+) and HBV-negative (HBV-) HCC tissues showed different microbial network patterns, with Bacteroides enrichment in HBV+ tissues being associated with HCC prognosis. HBV is associated with clinicopathological features and serves as an independent prognostic factor in HCC. The study underscores the microbiota's complexity in HCC and the potential of HBV as a prognostic biomarker post-surgery. This study provides critical insights into the relationship between the microbiota within the TME and HCC, a leading cause of cancer-related mortality. By identifying distinct microbiome profiles in HCC patients, particularly the enrichment of Bacteroides in HBV-positive tissues, our research not only uncovers the complexity of microbial interactions in liver cancer but also highlights the potential of using HBV status as a prognostic biomarker. This could significantly inform personalized treatment strategies and improve clinical outcomes for HCC patients, emphasizing the relevance of microbiome-based diagnostics and therapies in oncology.IMPORTANCEIn our study of the tumor microenvironment (TME) in hepatocellular carcinoma (HCC), we used DNA sequencing of bacterial 16S rRNA genes to analyze microbial compositions in tumor, adjacent tumor, and normal tissues from 213 liver cancer patients. Fluorescence in situ hybridization confirmed the presence of microbiota within tumors. Our results showed significant differences in microbiome profiles between tumor and normal tissues, with increased abundance of Bacteroides, Ochrobactrum, Akkermansia, and Lactobacillus in the HCC TME. Hepatitis B virus (HBV) status further stratified these differences, with Bacteroides significantly enriched in HBV-positive tissues and correlating with patient prognosis. Additionally, Bacteroides and Akkermansia showed interdependent population changes. Clinicopathological features, such as tumor size, were associated with HBV status, identifying HBV infection as an independent prognostic factor. These findings highlight the HCC microbiota's complexity and suggest HBV status as a potential prognostic biomarker, opening avenues for personalized therapeutic strategies.

The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma

The incidence of hepatitis B virus (HBV) infection in dialysis populations has declined over recent decades, largely because of improvements in infection control and widespread implementation of HBV vaccination. Regardless, outbreaks of infection continue to occur in dialysis units, and prevalence rates remain unacceptably high. For a variety of reasons, dialysis patients are at increased risk of acquiring HBV. They also demonstrate different disease manifestations compared with healthy individuals and are more likely to progress to chronic carriage. This paper will review the epidemiology, modes of transmission and diagnosis of HBV in this population. Prevention and treatment will be discussed, with a specific focus on strategies to improve vaccination response, new therapeutic options and selection of patients for therapy.

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality and healthcare expenditure in patients with chronic liver disease. There are no consensus guidelines on diagnosis and management of HCC in India. The Indian National Association for Study of the Liver (INASL) set up a Task-Force on HCC in 2011, with a mandate to develop consensus guidelines for diagnosis and management of HCC, relevant to disease patterns and clinical practices in India. The Task-Force first identified various contentious issues on various aspects of HCC and these issues were allotted to individual members of the Task-Force who reviewed them in detail. The Task-Force used the Oxford Center for Evidence Based Medicine-Levels of Evidence of 2009 for developing an evidence-based approach. A 2-day round table discussion was held on 9th and 10th February, 2013 at Puri, Odisha, to discuss, debate, and finalize the consensus statements. The members of the Task-Force reviewed and discussed the existing literature at this meeting and formulated the INASL consensus statements for each of the issues. We present here the INASL consensus guidelines (The Puri Recommendations) on prevention, diagnosis and management of HCC in India.

Occult HBV infection—both hidden and mysterious

Epidemiology of hepatitis B in Europe and worldwide.

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and is particularly prevalent in China. China is also a hyperendemic area for hepatitis B virus (HBV) infection. Although a strong association between HBV infection and HCC has been established previously, the role of hepatitis C virus (HCV) infection and the interaction between HBV and HCV in the development of HCC has not been adequately explored. The major objective of this study is to determine the relationship between HBV or HCV infection and HCC by use of case-control study in Henan, China. In all, 152 HCC patients and 115 control patients were collected from four hospitals in Henan, China between January 1994 and October 1995. The demographic characteristics of the two groups were comparable. In further analysis, a 1:1 pair-matched case-control study was performed. Of 152 HCC patients, 113 were randomly selected to be pair-matched by sex and age (+/-5 years) to controls with non-hepatic disease. All the cases and controls were interviewed during hospitalization by two specially trained interviewers using a standard questionnaire. All sera were tested for HBV and HCV markers. Odds ratios (OR) and 95% CI for HCC risk factors were calculated by logistic regression model controlling for possible confounding factors such as sex and age. The multivariate analysis was done on the basis of the univariate analysis. The results of this study indicated that the prevalence of hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) were much higher in HCC patients (63.2% and 11.2% respectively) than in the control patients (5.2%, 3.5%). The difference between two groups was significant (P < 0.05). Risk factor analysis revealed that both HBV and HCV infection were important factors for HCC in Henan, China and HBV appeared to have a key role in the development of HCC. Odds ratios of HBsAg and HBV infection were 28.82 (95% CI: 11.18-78.78) and 31.22 (95% CI: 13.86-72.15), respectively. Moreover, the risk of developing HCC increased significantly and showed an additive effect when both viral markers of HBV and HCV infection were considered (OR = 42.85). Results from the 1:1 pair-matched case-control study also showed that HBV infection was an important risk factor for HCC, which was consistent with the results from the group-matched case-control study. This is the first reported case-control study of HCC in Henan, China. This study provides further evidence that chronic HBV infection is strongly associated with the development of HCC among this population. Our results have demonstrated that HCV and HBV infection are independent and probably additive risk factors for HCC.

334 Background: Currently, combined immunotherapy of atezolizumab (anti-PD-L1 antibody) plus bevacizumab (a humanized anti-VEGF monoclonal antibody) is the standard first-line treatment in patients with advanced hepatocellular carcinoma (HCC). At the threshold of this new era, there is limited information about tumor microenvironment (TME) in advanced HCC. Several studies on TME in HCC have analyzed samples obtained via hepatic resection. In general, hepatic resection is indicated for patients with limited size and number of intrahepatic nodules, i.e., early stage HCC. In contrast, most patients who have an indication for systemic therapy have developed macroscopic vascular invasion (MVI) or/and extrahepatic metastasis, namely in advanced stage HCC. Progression from an early stage HCC to an advanced stage HCC involves a lengthy clinical course, therefore, the TME at the time of initial diagnosis may differ from that at the time of systemic therapy indication. The present study was aimed to analyze the TME by using needle biopsy samples obtained prior to initiation of systemic therapy in patients with advanced HCC. Methods: Between March 2019 and May 2020, 80 patients underwent liver tumor biopsy at the time of indication for systemic chemotherapy. HCC was confirmed via pathological examination in 70 patients and their samples were analyzed. Microsatellite instability (MSI) was evaluated using polymerase chain reaction. Programed death-ligand 1 (PD-L1) expression and the levels of tumor-infiltrating lymphocytes (TIL) were evaluated using immunohistochemical staining. PD-L1 expression was defined as per the tumor proportion score (TPS; the number of PD-L1-positive cells/total number of tumor cells) and was classified as low (TPS &lt; 1%) or high (TPS &gt;1%). Levels of TIL were defined as the mean number of CD8-positive lymphocytes in the tumor per 1 mm2 and classified as low or high using the median value. Results: Out of the 70 tumors, one was MSI-high and 69 were MSI-negative. The PD-L1 expression was &lt; 1% in 50 samples, 1%–10% in 12, 11%–20% in 7, and 21%–30% in 1. The median level of TIL was 266/mm2. PD-L1highTILhighwas present in 20.0%, PD-L1lowTILlowin 38.5%, PD-L1highTILlowin 8.6%, and PD-L1lowTILhighin 32.9%. In the MSI-high tumor, PD-L1 expression was &lt; 1% and the level of TIL was 142/mm2. High PD-L1 expression and high levels of TIL were associated with hepatitis C virus infection, high alpha-fetoprotein levels, and presence of MVI respectively. We are currently performing RNA-sequencing in order to obtain more details about TME in patients with advanced HCC. Conclusions: MSI-high advanced HCC was detected in 1.4% patients and was not necessarily associated with a “hot” immune microenvironment. PD-L1 expression and levels of TIL were associated with some clinical parameters. In the present study, we also reported the changes in the TME over time.

Time-dependent events in natural history of occult hepatitis B virus infection: the importance of population-based long-term follow-up study with repeated measurements

Introduction

See article on page 789 Worldwide, 170 million people are infected with hepatitis C virus (HCV) persistently. Like hepatitis B virus (HBV) that infects approximately 350 million individuals in the world, HCV is transmitted parenterally, typically by transfusions and illicit intravenous drugs. The differences between these two hepatitis viruses are that HBV infection, except when introduced to hosts in infancy, goes on to become chronic in only a few percent, while HCV infection evolves into being chronic much more frequently and persists in approximately 70% of the infected. In contrast to chronic hepatitis B that is mostly self-limited, chronic hepatitis C is an ever progressive disease. Consequently, hepatocellular carcinoma (HCC), the most dreadful sequel of persistent hepatitis virus infection, develops much more often in individuals chronically infected with HCV than HBV. Unlike HBV, which is a DNA virus and integrated into the host genome, HCV, being an RNA virus not reverse-transcribed to DNA, is hardly carcinogenic per se. Hence, HCC almost always develops in the background of chronic hepatitis C and associated liver cirrhosis in the long run. It is estimated to take 30 years before HCC develops in patients who are followed up and who are presumed to have contracted the infection by transfusions.1 In comparison with other malignancies, HCC is unique in that the individuals at risk for developing it can be identified and followed closely; they are persistently infected with HBV or HCV and suffering from chronic hepatitis. Moreover, therapeutic interventions for preventing HCC are possible by either exterminating hepatitis viruses or controlling the inflammatory process leading to hepatocarcinogenesis. Hepatocellular carcinoma associated with hepatitis virus infections is most prevalent in Asia and Africa. Experiences with recognition and prevention of HCV-associated HCC, which have accumulated in Japan during the past 30 years, are hoped to help plan strategies in Western countries where HCV infection prevails at the present and will advance into HCC in the foreseeable decades. In Japan, HCC occurs at an incidence of 35 cases per 100 000 people annually at present, which is much higher than that in Europe and the United States of America. However, the incidence of HCC was not so high 30 years ago even in Japan. Figure 1 depicts the annual death of patients caused by HCC, estimated from the national reports issued biyearly. A clear trend for the increase in death because of HCC is seen since 1975. Etiologic analysis became possible from the mid-1970s for HBV, and as of 1990 for HCV, which had been classified in a non-A, non-B category until then. Increasing incidence of death because of hepatocellular carcinoma in Japan. (▪) Represents the cases positive for hepatitis B surface antigen (HBsAg) and () represents the cases positive for antibodies to hepatitis C virus (anti-HCV). The cases negative for both HBsAg and anti-HCV are presented by (□). Over the past 25 years, the proportion of HBV infection, identified by hepatitis B surface antigen (HBsAg) in serum, has stayed constant and accounted for less than five deaths caused by HCC per 100 000 people/ year. A rapid biyearly increase since 1975 is ascribable to the etiology that is unrelated to HBV, although a role of HBV is not to be excluded in the patients seronegative for HBsAg. Serologic tests for HCV infection by antibody to HCV (anti-HCV) and HCV-RNA introduced since 1990 have disclosed that by far the highest number of cases negative for HBsAg were infected with HCV. Today, markers of ongoing HCV are detected in approximately 80% and those of HBV in approximately 20% in HCC patients in Japan; the etiology remains unknown in only a few percent. Taken together, HCV is reasonably considered to be responsible for the rapid biyearly increase of death caused by HCC ever since 1975 in Japan. The reason why HCV has spread in the past, eventuating in a high incidence of HCV-associated HCC today, is not yet fully established. According to the reasoning by Dr Hiroshi Yoshizawa (pers. comm., 2000) of the University of Hiroshima, the following scenario is likely. He postulates an HCV epidemic in a restricted population in Japan that started just after the end of World War II in 1945. Intravenous injections with methamphetamine was popular among ex-soldiers to keep them awake and promote their fighting spirit in the war. It would not have taken much time for them to be infected with HCV, with transmission expected from HCV infection among illicit intravenous drug users. The subpopulation kept selling blood, so as to support themselves and secure intravenous drugs, which unselectively transmitted HCV infection to the recipients of transfusions. In that age, tuberculosis prevailed in Japan, and plastic surgery was popular; it involved transfusions for dissemination of HCV among the patients with pulmonary tuberculosis. In addition, HCV is considered to have spread by medical and paramedical practices by means of contaminated needles and syringes until recently. Besides all these transmission routes, the post-transfusion non-A, non-B hepatitis was not contained until November, 1989 when the exclusion of blood units positive for anti-HCV was introduced in Japan; it was earlier than any other countries in the world. Now that post-transfusion hepatitis C is completely prevented, and with a fortunate uncommon abuse of illicit drugs, de novo HCV infection has become infrequent in Japan. Dr Yoshizawa predicts that the incidence of HCV-associated HCC will reach a plateau by the year 2010, and then decline thereafter. How and when HCV infection started to prevail in Europe and the United States of America is not known. In the wake of what is ongoing in Japan, it is not difficult to speculate that turmoil with the Vietnam War during the 1960s would have had some impact on a rapid spread of HCV in the United States of America. Should that be the case, the experiences with HCV-associated HCC in Japan would be mirrored in the United States of America, with an expected time lag of approximately 20 years (Fig. 1). There are two means of preventing HCC that is associated with HBV or HCV infection. One is to halt the invasion at the coast, which is being accomplished for HBV infection. In Asia, the persistent carrier state of HBV in immune-competent individuals is established by the perinatal transmission of HBV to babies from mothers who are seropositive for hepatitis B e antigen (HBeAg). Since 1986, the Japanese Ministry of Health and Welfare launched a national program to prevent the perinatal HBV infection by protecting the babies born to HBeAg-positive carrier mothers with a combined hepatitis B immune globulin and hepatitis B vaccine. As a consequence, the perinatal HBV transmission decreased from approximately 4000 cases to merely a few hundred cases per year nowadays; the immunoprophylaxis does not work on approximately 4% of babies who receive it because of transplacental infection in utero. The screening of blood units for HBsAg was started in 1972, and it has consequently decreased the incidence of post-transfusion HBV infection in Japan dramatically. The residual risk of transmitting HBV by transfusions has been curtailed by implementing tests for hepatitis B core antibodies (anti-HBc) in 1989, as well as tests for HBV-DNA by using molecular biological techniques starting at the turn of the millennium. Both these tests can identify blood donors in the ‘window’ period of HBV infection before serological markers such as HBsAg and anti-HBc appear in the circulation. Likewise, the screening of blood donors for anti-HCV since 1989, and better still for HCV-RNA initiated very recently, has been most efficient and decreased the risk of post-transfusion hepatitis C infinitely to zero. At present, however, there are no means of preventing perinatal transmission of HCV that occurs in approximately 4% of babies born to carrier-mothers who are not coinfected with human immunodeficiency virus type 1. Passive immunoprophylaxis with anti-HCV immunoglobulins and active immunoprophylaxis with hepatitis C vaccines are eagerly awaited, not only to prevent perinatal transmission, but also for the protection of groups with increased professional or recreational risk of contracting HCV infection. The other approach for prevention of HCC, associated with HBV or HCV infection, is directed towards patients with chronic viral hepatitis who have already been infected and run a high risk of developing HCC. The mechanism of how HCC develops in patients with chronic viral hepatitis/cirrhosis is not known. The present consensus is that necroinflammatory changes in the liver of patients with chronic viral hepatitis endows it with a ‘hypercarcinogenic state’,2 probably through regenerative force and oxidative injury to host DNA in hepatocytes. Hence, two ways of preventing HCC in the high-risk population can be envisaged, one of which is radical, while the other is palliative. Ideally, HBV or HCV should be eradicated from the patients for radical cure of chronic viral hepatitis. This can be achieved by interferons in concert with lamivudine for HBV, and in combination with ribavirin for HCV. Accumulating lines of evidence indicate that HCC occurs rarely, if ever, in the patients who have cleared HCV from their sera.3 A current impediment to this protocol is that not all patients respond to these antiviral therapies by clearing viral infections. A complete and sustained response to antiviral therapies is accomplished in one-half of the patients infected with HCV, at best. Hence, attending physicians are left with the other half of patients in whom HCV infection continues accompanied by active liver diseases along with ongoing necroinflammatory changes and increasing fibrosis. Licorice is a crude extract from the root of Glycyrrhiza glabra, and has been a popular Chinese medicine with a history going back to the BC era. The active principle of licorice is glycyrrhizin, which is composed of one molecule of glycyrrhetinic acid and two molecules of glucuronic acid. The medicine has been commercially available as Stronger Neo-Minophagen C (SNMC; Minophagen Pharmaceutical Co., Tokyo, Japan) for the past 60 years, as an aqueous solution containing 40 mg glycyrrhizin supplemented with glycine (400 mg) and cysteine (20 mg) in a 20 mL ampoule. It has mainly been used for the treatment of allergic diseases, represented by chronic dermatitis and urticaria. Since the late 1960s, SNMC has gained increasing attention for its possible use in patients with chronic hepatitis. In 1977, Suzuki et al. conducted the first prospective double-blind and placebo-controlled trial for the efficacy of SNMC on a cohort of 133 patients with chronic hepatitis in Japan, most of whom were infected with HCV in retrospect.4 Their results were introduced to the Western medical society in 1983. They found that SNMC significantly reduces the levels of alanine aminotransferase (ALT) and γ-glutamyl transpeptidase in the patients who received SNMC during 4 weeks of the trial. The effects of SNMC were transient, however, and liver enzymes swiftly returned to pretreatment levels after the withdrawal of SNMC. There is an apparent dose-effect of SNMC in nomalization of liver function tests. A higher efficacy in decreasing ALT levels is observed in patients with chronic hepatitis C who received 100 mL (five ampoules) than those who received 40 mL (two ampoules) of SNMC intravenously.5 A prospective trial starting with a daily injection of 100 mL SNMC has been conducted by Arase et al.6 in a liver clinic in Japan headed by Dr Hiromitsu Kumada, for a timespan extending to 15–20 years. They gave SNMC to 84 patients for whom a daily intravenous injection was feasible, and oral herbal medicines to the other 109 patients who did not have handy facilities for a daily injection around them. They found that the patients who received SNMC ran a 2.5-fold lower risk of developing HCC than those who did not receive SNMC. Therefore, they have demonstrated the ability of SNMC to prevent HCC, most likely by controlling or retarding necroinflammatory and fibrotic processes that occur with continuing HCV infection in the liver. It is not known how SNMC inhibits the progression of chronic hepatitis C. It does not seem to have antiviral effects, because HCV-RNA titers in serum do not change appreciably in patients who receive it.7 Two distinct actions of SNMC are postulated. One is its immediate effects capable of decreasing ALT levels within a matter of hours, and may be ascribed to the cytoprotective capacity of glycyrrhizin. The other pharmaceutical effects include an anti-inflammatory activity of glycyrrhetinic acid, representing the final metabolite of glycyrrhizin. Orally administered glycyrrhizin is converted to glycyrrhetinic acid in the intestine and then absorbed. The unavailability of glycyrrhizin in the circulation would be responsible for less efficacy of orally than parenterally administered glycyrrhizin preparations. Pseudo-aldosteronism has long been noted in individuals on a large dose of glycyrrhizin. The mechanism how it induces pseudo-aldosteronism was determined only recently.8 Glycyrrhetinic acid, as well as the metabolite of glycyrrhizin with one glucronic acid,9 interferes with the enzyme that catalyzes the conversion of cortisol to cortisone. Resulting excessive cortisol stimulates the mineralocorticoid receptor leading to pseudo-aldosteronism. Therefore, in principle, glycyrrhizin would have much less activity to induce pseudo-aldosteronism than its metabolites with one or no glucuronic acid components on them. This seems to be the case because pseudo-aldosteronism is more frequent in patients who receive an oral than an intravenous preparation of glycyrrhizin. The report in this issue seems to resolve undue concerns for an activity of SNMC to induce pseudo-aldosteronism. van Rossum et al. placed patients with chronic hepatitis C on two SNMC regimens with five ampoules at six times a week (weekly dose: 1200 mg) or six ampoules at three times a week (720 mg) for 4 weeks.10 None of the patients developed full-blown pseudo-aldosteronism; only a few of them on a higher dose of SNMC showed minor reversible symptoms of pseudo-aldosteronism without the need for medication. Based on their observation, they warn against a weekly dose of SNMC greater than 1200 mg. Arase et al. noted moderate hypokalemia (< 3 mEq/mL) in nine (11%) patients, and increased blood pressure (> 160/90 mmHg) in three (4%) of the 84 patients who were started on a daily dose of 100 mL SNMC (weekly dose: 1400 mg) during a period ranging from 15 to 20 years.6 As the indication of SNMC widens in the future, pseudo-aldosteronism occurring in minor predisposed individuals may come to the fore. Physicians have to keep their eyes open to the signs and symptoms of pseudo-aldosteronism, which are corrected easily and safely by antagonists to aldosterone. More than 90% of the patients with HCV-associated liver cirrhosis die of HCC developing later in their lives. With the advent of modern medicine, it has become increasingly less frequent for patients to die because of the complications of decompensated liver cirrhosis, such as hepatic encephalopathy and variceal bleeding. Hence, the main goal of treatment would be to prevent HCC or retard its occurrence until or close to the life expectancy of the patient. Antiviral agents are the principal resort to this end, because they are capable of eradicating the cause of hepatocarcinogenesis. For the patients who poorly respond to antiviral therapies, other measures need to be used to protect them from HCC. Although intravenous glycyrrhizin (SNMC) can contribute toward this goal, its use on chronic viral hepatitis has been restricted to Japan, Holland, China and Germany so far.4–8,10–12 The administration of SNMC through intravenous injection poses considerable constraints against its life-long use in patients with chronic hepatitis C. The development of oral or intramuscular preparations of SNMC is awaited, for an easier administration to millions of people infected with HCV over the world in whom the development of HCC has to be prevented or delayed.

PD-L1 promotes myofibroblastic activation of hepatic stellate cells by distinct mechanisms selective for TGF-β receptor I versus II.