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Chronic hepatitis B infection (CHB) affects 300 million people worldwide and is being targeted by the United Nations 2030 Sustainable Development Goals (SDGs) and the World Health Organisation (WHO), working towards elimination of hepatitis B virus (HBV) as a public health threat. In this piece, we explore the evidence and potential impact of peer support to enhance and promote interventions for people living with CHB. Peer support workers (PSWs) are those with lived experience of an infection, condition or situation who work to provide support for others, aiming to improve education, prevention, treatment and other clinical interventions and to reduce the physical, psychological and social impacts of disease. Peer support has been shown to be a valuable tool for improving health outcomes for people living with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), but to date has not been widely available for communities affected by HBV. HBV disproportionately affects vulnerable and marginalised populations, who could benefit from PSWs to help them navigate complicated systems and provide advocacy, tackle stigma, improve education and representation, and optimise access to treatment and continuity of care. The scale up of peer support must provide structured and supportive career pathways for PSWs, account for social and cultural needs of different communities, adapt to differing healthcare systems and provide flexibility in approaches to care. Investment in peer support for people living with CHB could increase diagnosis, improve retention in care, and support design and roll out of interventions that can contribute to global elimination goals.
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Hepatite B Crônica , Grupo Associado , Apoio Social , Humanos , Hepatite B Crônica/terapia , Hepatite B Crônica/psicologiaRESUMO
Diagnosing and treating chronic hepatitis B virus (HBV) infection are key interventions to support progress towards elimination of viral hepatitis by 2030. Although nucleos/tide analogue (NA) therapy is typically highly effective, challenges remain for viral load (VL) suppression, including medication access, incomplete adherence and drug resistance. We present a case of a long-term HBV and HIV coinfected adult prescribed with sequential NA therapy regimens, with episodes of breakthrough viraemia. Multiple factors contribute to virological breakthrough, including exposure to old NA agents, initial high HBV VL, therapy interruptions, intercurrent illnesses and potential contribution from resistance mutations. The case underscores the importance of individualised treatment approaches and adherence support in achieving HBV suppression. Furthermore, it emphasises the need for improved clinical pathways addressing education, support and access to care, particularly for marginalised populations. Comprehensive data collection inclusive of under-represented individuals is crucial for maintaining retention in the care cascade and informing effective interventions.
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Antivirais , Infecções por HIV , Vírus da Hepatite B , Hepatite B Crônica , Carga Viral , Viremia , Adulto , Humanos , Pessoa de Meia-Idade , Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Farmacorresistência Viral , Guanina/análogos & derivados , Guanina/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Fatores de Risco , Viremia/tratamento farmacológicoRESUMO
In their never-ending quest towards persistence within their host, hepatitis viruses have developed numerous ways to counteract the liver innate immunity. This review highlights the different and common mechanisms employed by these viruses to (i) establish in the liver (passive entry or active evasion from immune recognition) and (ii) actively inhibit the innate immune response (ie modulation of pattern recognition receptor expression and/or signalling pathways, modulation of interferon response and modulation of immune cells count or phenotype).
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Imunidade Inata , Vírus , Interferons , Fígado , Receptores de Reconhecimento de PadrãoRESUMO
BACKGROUND & AIMS: Liver macrophages can be involved in both pathogen clearance and/or pathogenesis. To get further insight on their role during chronic hepatitis B virus (HBV) infections, our aim was to phenotypically and functionally characterize in vivo and ex vivo the interplay between HBV, primary human liver macrophages (PLMs) and primary blood monocytes differentiated into pro-inflammatory or anti-inflammatory macrophages (M1-MDMs or M2-MDMs, respectively). METHODS: PLMs or primary blood monocytes, either ex vivo differentiated into M1-MDMs or M2-MDMs, were exposed to HBV and their activation followed by ELISA or quantitative reverse transcription PCR (RT-qPCR). Liver biopsies from HBV-infected patients were analysed by RT-qPCR or immunohistochemistry. Viral parameters in HBV-infected primary human hepatocytes and differentiated HepaRG cells were followed by ELISA, qPCR and RT-qPCR analyses. RESULTS: HBc protein was present within the macrophages of liver biopsies taken from HBV-infected patients. Macrophages from HBV-infected patients also expressed higher levels of anti-inflammatory macrophage markers than those from non-infected patients. Ex vivo exposure of naive PLMs to HBV led to reduced secretion of pro-inflammatory cytokines. Upon exposure to HBV or HBV-producing cells during differentiation and activation, M1-MDMs secreted less IL-6 and IL-1ß, whereas M2-MDMs secreted more IL-10 when exposed to HBV during activation. Finally, cytokines produced by M1-MDMs, but not those produced by HBV-exposed M1-MDMs, decreased HBV infection of hepatocytes. CONCLUSIONS: Altogether, our data strongly suggest that HBV modulates liver macrophage functions to favour the establishment of infection. LAY SUMMARY: Hepatitis B virus modulates liver macrophage function in order to favour the establishment and likely maintenance of infection. It impairs the production of the antiviral cytokine IL-1ß, while promoting that of IL-10 in the microenvironment. This phenotype can be recapitulated in naive liver macrophages or monocyte-derived-macrophages ex vivo by short exposure to the virus or cells replicating the virus, thus suggesting an "easy to implement" mechanism of inhibition.
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Diferenciação Celular/imunologia , Vírus da Hepatite B/fisiologia , Hepatite B Crônica , Células de Kupffer , Ativação de Macrófagos/imunologia , Monócitos , Células Cultivadas , DNA Viral/isolamento & purificação , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Humanos , Imuno-Histoquímica , Imunomodulação , Interleucina-10 , Interleucina-1beta , Células de Kupffer/imunologia , Células de Kupffer/patologia , Monócitos/imunologia , Monócitos/patologia , Sistema Fagocitário Mononuclear/imunologiaRESUMO
Introduction: The World Health Organisation (WHO) has set targets for the elimination of Hepatitis B virus (HBV), which include preventing new infections and reducing deaths. We explored beliefs, behaviours and barriers to diagnosis, prevention and treatment for people living with HBV infection (PLWHB) and those with liver disease in a rural South African population in KwaZulu-Natal, to gather information to inform research and support the development of improved clinical and public health services. Methods: Using an interdisciplinary approach (combining public engagement, social science, clinical and laboratory team members) we conducted a community dialogue with members of the Africa Health Research Institute (AHRI) Community Advisory Board (CAB). Notes from the discussions were used to write up an account from which themes were identified during a team debrief session for data analysis. Results: There was a lack of knowledge and awareness of HBV infection and transmission and prevention amongst CAB members, also reported among community members and healthcare workers. The participants recognised liver disease symptoms. Perceived causes of liver disease reported by the CAB were alcohol and non-adherence to HIV treatment. Barriers to care included stigma, poverty, and delays in referrals for HBV diagnosis and management. Conclusion: Understanding barriers to care is important to shape future services for diagnosis, treatment and prevention of HBV and liver disease which are accessible, affordable and acceptable to the local population. Education, awareness and advocacy for improved liver health care pathways are required to make them effective for local communities.
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BACKGROUND: As nucleos/tide analogue (NA) therapy (e.g. entecavir and tenofovir) for chronic Hepatitis B virus (HBV) infection becomes more widely indicated and available, understanding drug resistance is essential. A systematic review to quantify resistance to these agents has not previously been undertaken. METHODS: We performed a systematic review and random-effects meta-analysis to estimate the risk of HBV resistance to entecavir and tenofovir. We searched nine databases up to 29-Aug-23. We included studies of HBV infection featuring >10 individuals, written in English, reporting treatment ≥48 weeks, with assessment of HBV resistance based on viral sequence data. Data were analysed according to prior exposure history to NA, and choice of NA agent. Analyses were performed in R. FINDINGS: 62 studies involving a total of 12,358 participants were included. For entecavir, in treatment-naive individuals (22 studies; 4326 individuals), resistance increased over time to 0.9 % at ≥5 years (95 %CI 0.1-2.3 %), and resistance was increased in NA-experienced individuals (18 studies; 1112 individuals), to 20.1 % (95 %CI 1.6-50.1 %) at ≥5 years. For tenofovir, pooled resistance risk was 0.0 % at all time points, whether previously NA naive (11 studies; 3778 individuals) or experienced (19 studies; 2059 individuals). There was a lack of consistent definitions, poor global representation and insufficient metadata to support subgroup analysis. INTERPRETATION: We have generated the first pooled estimates of HBV entecavir and tenofovir resistance over time. HBV resistance to entecavir in treatment-experienced groups in particular may represent a clinical and public health challenge. To date, tenofovir appears to have an excellent resistance profile, but due to data gaps, we caution that existing studies under-estimate the true real-world risk of resistance. Robust prospective data collection is crucial to reduce health inequities and reduce blind-spots in surveillance as treatment is rolled out more widely.
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The WHO African region bears a disproportionate burden of morbidity and mortality related to chronic hepatitis B virus (HBV) infection and accounts for an estimated 70% of new HBV infections worldwide. We investigated the extent to which HBV clinical trials represented populations in this region by searching the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for interventional clinical trials published in English between database inception and May 29, 2023, using the search term "Hepatitis B". We identified 1804 unique clinical trials, of which 18 (1·0%) recorded involvement of the WHO African region. There is no evidence that the number of HBV clinical trials in this region has improved over time. The diversity of new interventions and industry sponsorship in the WHO African region were low, with trials of HBV comparing poorly with those of other endemic infectious diseases (eg, malaria, HIV, and SARS-CoV-2). HBV research and clinical trial investigations have neglected the WHO African region, leading to profound health inequities. HBV clinical trials are urgently needed to evaluate the efficacy of newly discovered therapeutics and to ensure that interventions can be equitably distributed and deployed as they become available.
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Hepatite B Crônica , Hepatite B , Humanos , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Hepatite B/tratamento farmacológico , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Organização Mundial da SaúdeRESUMO
Chronic hepatitis D is the most aggressive form of chronic viral hepatitis. It is caused by super-infection of hepatitis B virus (HBV)-infected hepatocytes with hepatitis D virus (HDV). While the recent conditional approval of bulevirtide for HDV treatment offers a new therapeutic modality in Europe, there is an unmet medical need to further improve therapy. A more detailed characterization of virus-host interactions is needed for the identification of novel therapeutic targets. Addressing this need, we engineered a new stably-transformed cell line, named HuH7-2C8D, producing high titer recombinant HDV and allowing the study of viral particles morphogenesis and infectivity. Using this culture system, where viral propagation by re-infection is limited, we observed an increased accumulation of edited version of the viral genomes within secreted HDV viral particles over time that is accompanied with a decrease in viral particle infectivity. We confirmed the interaction of HDV proteins with a previously described host factor in HuH7-2C8D cells and additionally showed that these cells are suitable for co-culture assays with other cell types such as macrophages. Finally, the use of HuH7-2C8D cells allowed to confirm the dual antiviral activity of farnesyl transferase inhibitors, including the clinical candidate lonafarnib, against HDV. In conclusion, we have established an easy-to-handle cell culture model to investigate HDV replication, morphogenesis, and host interactions. HuH7-2C8D cells are also suitable for high-throughput antiviral screening assays for the development of new therapeutic strategies.
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Vírus Delta da Hepatite , Replicação Viral , Vírus Delta da Hepatite/genética , Linhagem Celular , Vírus da Hepatite B , Antivirais/farmacologia , Descoberta de DrogasRESUMO
De novo immune responses are considered major challenges in gene therapy. With the aim to lower innate immune responses directly in cells targeted by adeno-associated virus (AAV) vectors, we equipped the vector capsid with a peptide known to interfere with Toll-like receptor signaling. Specifically, we genetically inserted in each of the 60 AAV2 capsid subunits the myeloid differentiation primary response 88 (MyD88)-derived peptide RDVLPGT, known to block MyD88 dimerization. Inserting the peptide neither interfered with capsid assembly nor with vector production yield. The novel capsid variant, AAV2.MB453, showed superior transduction efficiency compared to AAV2 in human monocyte-derived dendritic cells and in primary human hepatocyte cultures. In line with our hypothesis, AAV2.MB453 and AAV2 differed regarding innate immune response activation in primary human cells, particularly for type I interferons. Furthermore, mice treated with AAV2.MB453 showed significantly reduced CD8+ T cell responses against the transgene product for different administration routes and against the capsid following intramuscular administration. Moreover, humoral responses against the capsid were mitigated as indicated by delayed IgG2a antibody formation and an increased NAb50. To conclude, insertion of the MyD88-derived peptide into the AAV2 capsid improved early steps of host-vector interaction and reduced innate and adaptive immune responses.
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OBJECTIVES: Pegylated-interferon-alpha (Peg-IFNα), an injectable innate immune protein, is still used to treat chronically HBV-infected patients, despite its poor tolerability. Peg-IFNα has the advantage over nucleos(t)ide analogues (NAs) to be administrated in finite regimen and to lead to a higher HBsAg loss rate. Yet it would be interesting to improve the efficacy (i.e. while decreasing doses), or replace, this old medicine by novel small molecules/stimulators able to engage innate immune receptors in both HBV replicating hepatocytes and relevant innate immune cells. We have previously identified the Toll-Like-Receptor (TLR)-2 agonist Pam3CSK4 as such a potential novel immune stimulator. The aim of this study was to gain insights on the antiviral mechanisms of action of this agonist in in vitro cultivated human hepatocytes. DESIGN: We used in vitro models of HBV-infected cells, based on both primary human hepatocytes (PHH) and the non-transformed HepaRG cell line to investigate the MoA of Pam3SCK4 and identify relevant combinations with other approved or investigational drugs. RESULTS: We exhaustively described the inhibitory anti-HBV phenotypes induced by Pam3CSK4, which include a strong decrease in HBV RNA production (inhibition of synthesis and acceleration of decay) and cccDNA levels. We confirmed the long-lasting anti-HBV activity of this agonist, better described the kinetics of antiviral events, and demonstrated the specificity of action through the TLR1/2- NF-κB canonical-pathway. Moreover, we found that FEN-1 could be involved in the regulation and inhibitory phenotype on cccDNA levels. Finally, we identified the combination of Pam3CSK4 with IFNα or an investigational kinase inhibitor (called 1C8) as valuable strategies to reduce cccDNA levels and obtain a long-lasting anti-HBV effect in vitro. CONCLUSIONS: TLR2 agonists represent possible assets to improve the rate of HBV cure in patients. Further evaluations, including regulatory toxicity studies, are warranted to move toward clinical trials.
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Hepatite B Crônica , Hepatite B , Lipopeptídeos/farmacologia , Receptor 2 Toll-Like/agonistas , Antivirais/uso terapêutico , DNA Viral/metabolismo , Hepatite B/metabolismo , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatócitos , Humanos , Interferon-alfa/farmacologia , Receptor 1 Toll-Like/metabolismoRESUMO
Co-infection with the hepatitis B virus and hepatitis delta virus (HDV) leads to the most aggressive form of viral hepatitis. Using in vitro infection models, we confirmed that IL-1ß, a crucial innate immune molecule for pathogen control, was very potent against HBV from different genotypes. Additionally, we demonstrated for the first time a strong and rapid antiviral effect induced by very low doses of IL-1ß against HDV. In parallel, using co-culture assays, we demonstrated that monocytes exposed to HBV, and in particular to HBsAg, during differentiation into pro-inflammatory macrophages secreted less IL-1ß. Altogether, our data emphasize the importance of developing combined antiviral strategies that would, for instance, reduce the secretion of HBsAg and stimulate the immune system to produce endogenous IL-1ß efficient against both HBV and HDV.
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Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus Delta da Hepatite/efeitos dos fármacos , Interleucina-1beta/antagonistas & inibidores , Macrófagos/imunologia , Replicação Viral/efeitos dos fármacos , Antivirais/farmacologia , Coinfecção , Citocinas , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus Delta da Hepatite/genética , Hepatócitos , Humanos , Imunidade Inata , RNA Interferente PequenoRESUMO
Hepatitis B Virus (HBV) that infects liver parenchymal cells is responsible for severe liver diseases and co-infection with Hepatitis Delta Virus (HDV) leads to the most aggressive form of viral hepatitis. Even tough being different for their viral genome (relaxed circular partially double stranded DNA for HBV and circular RNA for HDV), HBV and HDV are both maintained as episomes in the nucleus of infected cells and use the cellular machinery for the transcription of their viral RNAs. We propose here an update on the current knowledge on HDV replication cycle that may eventually help to identify new antiviral targets.
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Núcleo Celular/virologia , Vírus Delta da Hepatite/genética , Vírus Delta da Hepatite/fisiologia , Hepatócitos/virologia , Replicação Viral , Animais , Coinfecção/virologia , Genoma Viral , Vírus da Hepatite B/fisiologia , Hepatite Viral Humana , Humanos , Camundongos , PlasmídeosRESUMO
Toll-like receptor 3 (TLR3) is an immune receptor that behaves like a death receptor in tumor cells, thereby providing an original target for cancer therapy. The therapeutic potential of TLR3 targeting in malignant mesothelioma, an aggressive and incurable neoplasia of the pleura and peritoneum, has so far not been addressed. We investigated TLR3 expression and sensitivity of human mesothelioma cell lines to the synthetic dsRNA Poly(I:C), alone or in combination with cisplatin, the gold standard chemotherapy in mesothelioma. Activation of TLR3 by Poly(I:C) induced apoptosis of 4/8 TLR3-positive cell lines but not of TLR3-negative cell lines. The combined cisplatin/Poly(I:C) treatment enhanced apoptosis of 3/4 Poly(I:C)-sensitive cell lines and overcame resistance to Poly(I:C) or cisplatin alone in 2/4 cell lines. Efficacy of the combined treatment relied on cisplatin-induced downregulation of c-FLIP, the main regulator of the extrinsic apoptotic pathway, leading to an enhanced caspase-8-mediated pathway. Of note, 6/6 primary cell samples isolated from patients with peritoneal mesothelioma expressed TLR3. Patient-derived cells were sensitive to Poly(I:C) alone while the combined cisplatin/Poly(I:C) treatment induced dramatic cell death. Our findings demonstrate that TLR3 targeting in combination with cisplatin presents an innovative therapeutic strategy in mesothelioma.