Abatacept is a biologic response modifier that is used in the treatment of refractory rheumatoid arthritis. This agent is not known to be associated with reactivation of hepatitis B virus (HBV) infection [[1]Carroll M.B. The impact of biologic response modifiers on hepatitis B virus infection.Expert Opin Biol Ther. 2011; 11: 533-544Crossref PubMed Scopus (23) Google Scholar]. We report a patient with occult HBV infection, who developed severe hepatitis B following treatment with abatacept. This 72-year-old woman, with a 30-year history of rheumatoid arthritis, was treated up to 2007 with methotrexate (15 mg/week, orally) and, periodically, with various non-steroidal anti-inflammatory drugs (NSAIDs). Prednisolone was used almost continuously during the last decade (10 mg daily). The patient also received the TNFα antagonist adalimumab (40 mg every other week) for a period of two years, up to September 2009, due to refractory, severe and progressive debilitating disease. Before starting adalimumab, she had serologic evidence of occult chronic HBV infection: negative HBsAg, positive HBcAb, positive HBsAb, negative HBeAg, and positive HBeAb. Serologic markers for HCV and HIV infections were negative. During this whole period, her AST and ALT serum levels remained below the upper limits of normal (ULN). Her rheumatoid arthritis remained resistant and severe, and abatacept (750 mg/dose, at 0, 2, 4 weeks and every 4 weeks thereafter) was started in October 2009, with concomitant use of prednisolone (10 mg daily) and leflunomide (20 mg daily). At the time, serum HBV DNA was undetectable. At the start of abatacept treatment, her serologic HBV markers were exactly the same as before administration of adalimumab, and her AST/ALT levels were below the ULN. The aminotransferase levels were routinely checked every three months, and remained within normal limits (WNL) up to April 2010. In July 2010, ALT was 1.76 × ULN and γGT was 1.62 × ULN. After two months, ALT was 2 × ULN, and became 2.76 × ULN in November 2010. At the time, γGT was 2.92 × ULN, and HBV serology remained unchanged. Abatacept and leflunomide were discontinued. Serum HBV DNA was found to be 12,000 IU/ml (COBAS TaqMan, analytical sensitivity 6 IU/ml). In January 2011, ALT was increased to 5 × ULN and γGT was 2.44 × ULN. The patient was hospitalized in February 2011, with ALT 11.58 × ULN, γGT 4.5 × ULN, bilirubin WNL, anti-HBs serum titer 328.4 mIU/ml, and serum HBsAg barely detectable (2.49 S/N) for the first time. A liver biopsy was performed. Six days after admission, ALT became 20.7 × ULN, γGT 5.7 × ULN, and bilirubin 2.2 × ULN (direct bilirubin: 86%). Serum HBV DNA was 437,000 IU/ml (by the same method), and treatment with tenofovir 300 mg/day was immediately started. In May 2011, AST, ALT, and γGT were WNL, under tenofovir treatment. Serum HBV DNA became undetectable in June 2011, four months after initiation of tenofovir treatment. Histologic examination of the liver biopsy specimen revealed hepatitis with severe lobular necroinflammatory activity and mild to moderate fibrosis. There was marked spotty necrosis, with many apoptotic and ballooned hepatocytes (Fig. 1A). Moderate steatosis was also present. Portal inflammatory cell infiltration was mild. Immunohistochemical stain for HBcAg showed extensive nuclear and cytoplasmic expression in hepatocytes, indicative of active viral replication (Fig. 1B). Immunohistochemical stain for HBsAg was negative. The basic medical treatments and laboratory data pertaining to HBV infection over time are depicted in Fig. 2. Abatacept is a soluble fusion protein which links the cytotoxic T-lymphocyte antigen-4 (CTLA-4) extracellular domain to the Fc region of the IgG molecule. CTLA-4 is an inhibitory T cell receptor, similar to CD28 in structure, expressed by activated and regulatory T cells (Tregs). CTLA-4 is constitutively expressed on CD4+ CD25+ Tregs, and such expression is important for Treg-mediated suppression of T cell proliferation. Through the inhibition of the co-stimulatory signaling of T cells in rheumatoid arthritis, abatacept has demonstrated clinical efficacy in multiple trials [[1]Carroll M.B. The impact of biologic response modifiers on hepatitis B virus infection.Expert Opin Biol Ther. 2011; 11: 533-544Crossref PubMed Scopus (23) Google Scholar]. Occult HBV infection is characterized by absence of HBsAg and HBV DNA in the serum; however, low level HBV replication may persist, and HBV DNA may be found in the liver. HBcAbs, with or without HBsAb, are detectable in the serum. Immunosuppression may lead to reactivation of HBV infection in these individuals. The outcome of a HBV infection varies according to the rigor of the immune response, a process that is regulated by a number of molecules, including the cell surface receptor CTLA-4. Some CTLA-4 haplotypes (−1722C, +49G) that lead to the activation of antiviral T cell responses were found to be associated with spontaneous clearance of HBV infection, whereas others leading to a decreased T cell response (i.e. +6230A) were associated with viral persistence [[2]Thio C.L. Mosbruger T.L. Kaslow R.A. Karp C.L. Strathdee S.A. Vlahov D. et al.Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection.J Virol. 2004; 78: 11258-11262Crossref PubMed Scopus (100) Google Scholar]. The CTLA-4 influences on the natural recovery from HBV infection are consistent with the emerging role of Tregs, possibly restraining the rigor of the immune response, in the pathogenesis of HBV liver disease. In our case, there was a time lag of two months between discontinuation of abatacept treatment and ALT flare, suggesting that reactivation of HBV infection and hepatitis evolved in parallel to gradual T cell immune reconstitution. It is also important to note that HBV reactivation occurred with HBsAb serum titers above 300 mIU/ml, a fact consistent with the key role of T cell functions in HBV immune control. Interestingly, cases of HBV reactivation due to the anti-CD20 B cell depleting agent rituximab have been described even with HBsAb serum titers of 300–1000 mIU/ml [[3]Tsutsumi Y. Ogasawara R. Kamihara Y. Ito S. Yamamoto Y. Tanaka J. et al.Rituximab administration and reactivation of HBV.Hepat Res Treat. 2010; 2010 ([Epub 2010 Dec 1]): 182067PubMed Google Scholar], a level considered to confer efficient neutralization of HBsAg and HBV circulating virion particles in the liver transplant setting. This is due to the fact that B cells not only produce antibodies, but also provide key co-stimulatory and cytokine signals for CD4+ cells, thus activating certain T cell functions. The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
The non‐structural (NS)5A protein of hepatitis C virus (HCV) is cleaved, after translation, by the NS3‐encoded zinc‐dependent serine proteinase, from the NS4B protein upstream and the NS5B protein downstream. The released, mature NS5A protein is a 56 000 MW phosphoprotein (p56), which also exists within infected cells in a hyperphosphorylated form (p58). The NS5A gene has a quasispecies distribution, meaning that various NS5A sequences co‐exist, in various proportions, in infected individuals. HCV NS5A appears to be located in cytoplasmic membranes surrounding the nucleus. Its precise functions are not known. HCV non‐structural proteins, including NS5A, form a large multiprotein replication complex, which probably directs the replication of the HCV genome. HCV NS5A lacking the 146 N‐terminal amino acids is a potent transcriptional activator in vitro . NS5A can also bind to single‐strand RNA‐dependent protein kinase (PKR) and inhibit its antiviral function. An ‘interferon (IFN) sensitivity‐determining region’ has recently been postulated in the NS5A protein central region in hepatitis C virus (HCV) genotype 1b, but strongly conflicting evidence has been published. In fact, there would seem to be no such region in the NS5A protein, even though NS5A plays an important and complex role in HCV resistance to IFN. Structure–function studies are required to identify precisely how NS5A and IFN interact.
Hepatocellular carcinoma (HCC) stands as a significant contributor to global cancer-related mortality. Chronic inflammation, often arising from diverse sources such as viral hepatitis, alcohol misuse, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH), profoundly influences HCC development. Within this context, the interplay of extracellular vesicles (EVs) gains prominence. EVs, encompassing exosomes and microvesicles, mediate cell-to-cell communication and cargo transfer, impacting various biological processes, including inflammation and cancer progression. Toll-like receptor 4 (TLR4), a key sentinel of the innate immune system, recognizes both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), thereby triggering diverse signaling cascades and pro-inflammatory cytokine release. The intricate involvement of the TLR4 signaling pathway in chronic liver disease and HCC pathogenesis is discussed in this study. Moreover, we delve into the therapeutic potential of modulating the TLR4 pathway using EVs as novel therapeutic agents for HCC. This review underscores the multifaceted role of EVs in the context of HCC and proposes innovative avenues for targeted interventions against this formidable disease.
Available treatments for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are associated with poor sustained responses. As a result, nucleoside and nucleotide analogues are typically continued indefinitely, a strategy associated with the risk of resistance and unknown long-term safety implications.We compared the efficacy and safety of peginterferon alfa-2a (180 microg once weekly) plus placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), and lamivudine alone in 177, 179, and 181 patients with HBeAg-negative chronic hepatitis B, respectively. Patients were treated for 48 weeks and followed for an additional 24 weeks.After 24 weeks of follow-up, the percentage of patients with normalization of alanine aminotransferase levels or hepatitis B virus (HBV) DNA levels below 20,000 copies per milliliter was significantly higher with peginterferon alfa-2a monotherapy (59 percent and 43 percent, respectively) and peginterferon alfa-2a plus lamivudine (60 percent and 44 percent) than with lamivudine monotherapy (44 percent, P=0.004 and P=0.003, respectively; and 29 percent, P=0.007 and P=0.003, respectively). Rates of sustained suppression of HBV DNA to below 400 copies per milliliter were 19 percent with peginterferon alfa-2a monotherapy, 20 percent with combination therapy, and 7 percent with lamivudine alone (P<0.001 for both comparisons with lamivudine alone). Loss of hepatitis B surface antigen occurred in 12 patients in the peginterferon groups, as compared with 0 patients in the group given lamivudine alone. Adverse events, including pyrexia, fatigue, myalgia, and headache, were less frequent with lamivudine monotherapy than with peginterferon alfa-2a monotherapy or combination therapy.Patients with HBeAg-negative chronic hepatitis B had significantly higher rates of response, sustained for 24 weeks after the cessation of therapy, with peginterferon alfa-2a than with lamivudine. The addition of lamivudine to peginterferon alfa-2a did not improve post-therapy response rates.
