Addressing hepatitis delta in primary care practices in the US: a narrative review.

OBJECTIVE: Infection with the hepatitis delta virus (HDV), a unique RNA virus that requires hepatitis B virus (HBV) antigens for its assembly, replication, and transmission, causes severe viral hepatitis. Compared to HBV monoinfection, HDV infection increases the risk of severe liver disease, necessity for liver transplant, and mortality. Global HDV prevalence estimates vary from 5% to 15% among persons with HBV, but screening guidelines for HDV are inconsistent; some recommend risk-based screening, while others recommend universal screening for all people with HBV. Among primary care providers (PCPs) in the US, there is a lack of awareness and/or insufficient adherence to current recommendations for the screening of HDV infection and management of chronic HDV. METHODS: Publications were obtained by conducting literature searches between July and August 2022 using the PubMed database and by manual searches of the retrieved literature for additional references. Information was synthesized to highlight HDV screening and management strategies for PCPs. Best practices for PCPs based on current guidelines and comanagement strategies for patients with HBV and HDV infection were summarized. RESULTS: We recommend universal screening for HDV in patients positive for hepatitis B surface antigen. Confirmed HDV infection should prompt evaluation by a liver specialist, if available, with whom the PCP can comanage the patient. PCPs should counsel patients on the expected course of the disease, lifestyle factors that may influence liver health, need for consistent disease monitoring and follow-up, and risk of disease transmission. Screening is suggested for sexual partners, household contacts, and family members, with HBV immunization recommended for those found to be susceptible. There are currently no US Food and Drug Administration-approved therapies for HDV infection; thus, management is limited to treatments for chronic HBV infection plus long-term monitoring of liver health. CONCLUSIONS: PCPs can be a valuable point of care for patients to access HDV/HBV screening, HBV immunization, and education, and can comanage patients with HBV and/or HDV infection.

Hepatitis delta virus (HDV) infection only occurs in the presence of hepatitis B virus (HBV) infection. People with an HDV infection are at higher risk for severe liver disease, liver transplant, and death compared to those who only have an HBV infection. The estimated global prevalence of HDV infection ranges from 5% to 15% among people living with HBV. These measurements vary due to different study methods, inconsistent HDV screening guidelines, and patient risk factors for infection.In the US, primary care providers (PCPs) play an important role in improving community access to HDV information and testing. However, poor funding and inadequate resources have created a lack of awareness and insufficient adherence by PCPs to current recommendations for screening and management of HDV infection. This narrative review aims to fill this gap by providing an overview of HDV infection, patient risk factors, and practice guidelines for PCPs.The recommendations for PCPs in this review include providing universal screening for HDV to people with an HBV infection, especially those at high risk. PCPs can educate and comanage patients with liver specialists. Topics to discuss with patients include expected disease outcomes, lifestyle factors that may influence liver health, and the need for consistent follow-up appointments. Patient risk of disease transmission can also be discussed to identify sexual partners, household contacts, and family members who will need screening and HBV vaccination. While there are no FDA-approved therapies for treating HDV infection, we provide an overview of available and emerging HDV treatments.

Reporte de caso: vasculitis leucocitoclastica como forma de presentación de hepatitis b crónica / Case report: leukocytoclastic vasculitis as presenting manifestation of chronic hepatitis b virus infection

La vasculitis leucocitoclástica, también denominada angeitis cutánea leucocitoclástica, es la forma más común de vasculitis. Si bien la mayoría de los casos son idiopáticos, entre los agentes etiológicos que podemos nombrar se encuentran los agentes infecciosos, las enfermedades del tejido conectivos, las reacciones de hipersensibilidad a medicamentos y las neoplasias solidas o hematológicas. Si bien los procesos infecciosos son una causa conocida de vasculitis leucocitoclástica, la infección por virus de Virus de hepatitis B (VHB) es muy infrecuente. Presentamos una mujer de 47 años, sin antecedentes patológicos previos, que consultó por artralgias en rodillas y tobillos, mialgias en gemelos y rash purpúrico con leve prurito en ambos miembros inferiores, de un mes de evolución. La biopsia cutánea de las lesiones de miembros inferiores fue compatible con vasculitis leucocitoclástica. La serología de hepatitis B fue positiva por lo que inició tratamiento antiviral con Tenofovir y Prednisona con buena evolución de sus lesiones cutáneas

Leukocytoclastic vasculitis, also called leukocytoclastic cutaneous angiitis, is the most common form of vasculitis. Although most cases are idiopathic, etiologic agents include infectious agents, connective tissue diseases, drug hypersensitivity reactions, and solid or hematologic malignancies. Although infectious processes are a known cause of leukocytoclastic vasculitis, hepatitis B virus (HBV) infection is very rare. We present a 47-year-old woman, with no previous pathologic history, who consulted for arthralgias in the knees and ankles, myalgia's and purpuric rash with mild pruritus in both lower limbs, of one month evolution. Skin biopsy of lower extremity lesions was compatible with leukocytoclastic vasculitis. Hepatitis B serology was positive, so she started antiviral treatment with tenofovir and prednisone with good evolution of her skin lesions

Sífilis, VIH y hepatitis B en el binomio madre-hijo. Caracterización de casos atendidos en centros de tercer nivel del interior de Córdoba / Syphilis, HIV and hepatitis B in the Mother-Child binomial

ntroducción: Las infecciones perinatales pueden transmi-tirse al feto y al recién nacido. Sífilis, VIH y hepatitis B deben tamizarse durante la gestación.Objetivo: Conocer la incidencia, prevalencia y manejo de sífilis, VIH y hepatitis B en el binomio madre/hijo. Comparar resultados con estadísticas oficiales.Materiales y métodos: Estudio retrospectivo, descriptivo y analítico, mediante revisión de historias clínicas del Sana-torio de la Cañada y Hospital Pasteur, Villa María, Córdoba. Período 01/12/2020 al 31/07/2021. Resultados: Se estudiaron 870 embarazos, la incidencia de sífilis materna fue 52,87/1000 embarazos, 76,1% de las gestantes eran menores de 30 años y hubo 41% de diag-nósticos tardíos. La incidencia de sífilis congénita fue de 18,3/1000 RN vivos. La incidencia de VIH materno fue de 6,89/1000 embarazos, 66,7% tenían menos de 30 años y el 77,7% tuvo carga viral indetectable al parto. El 100% de los RN expuestos fueron estudiados, todos con carga viral indetectable al nacimien-to. No hubo casos de hepatitis B.Conclusión: 6,3% de las embarazadas presentaron al me-nos una serología reactiva y el mayor porcentaje diagnós-tico se centró en menores de 30 años. La incidencia de sífilis congénita superó la provincial y nacional (18,3 vs. 1,18 vs. 1,14). El porcentaje de positividad de VIH materno superó al provincial. No hubo transmisión vertical de VIH al nacimiento. La prevalencia de hepatitis B fue menor a las oficiales

Introduction: Perinatal infections can be transmitted to the fetus and new-born. Syphilis, HIV and Hepatitis B must be monitored during pregnancy.Objective: To know incidence, prevalence and management of syphilis, HIV and Hepatitis B in the mother/child binomial. To compare results with official statistics.Materials and methods: Retrospective, descriptive and analytical study, through the review of medical records from Sanatorio La Cañada and Hospital Pasteur in Villa Maria, Cordoba. Period 12/01/2020 to 07/31/2021.Results 870 pregnancies were studied, the incidence of maternal syphilis was 57.87/1000 pregnancies, 76.1% of pregnant women were under 30 years old, and there were 41% late diagnoses. The incidence of congenital syphilis was 18.3/1000 live newborns. The incidence of maternal HIV was 6.89/1000 pregnancies, 66.7% were women under 30 years old and 77.7% had undetectable viral load at birth. 100% of the exposed newborns were studied, all with undetectable viral load at birth. There were no cases of Hepatitis B.Conclusion: 6.3% of pregnant women presented at least one reactive serology and the highest diagnostic percentage was focused on those under 30 years old. The incidence of congenital syphilis exceeded the provincial and national data (18.3 vs 1.18 vs 1.14). The percentage of maternal HIV positivity was superior to the provincial one. There was no vertical transmission of HIV at birth. The prevalence of Hepatitis B was less than the official ones.

PreS1- targeting chimeric antigen receptor T cells diminish HBV infection in liver humanized FRG mice.

Current therapies control but rarely achieve a cure for hepatitis B virus (HBV) infection. Restoration of the HBV-specific immunity by cell-based therapy represents a potential approach for a cure. In this study, we generated HBV specific CAR T cells based on an antibody 2H5-A14 targeting a preS1 region of the HBV large envelope protein. We show that the A14 CAR T cell is capable of killing hepatocytes infected by HBV with high specificity; adoptive transfer of A14 CAR T cells to HBV infected humanized FRG mice resulted in reductions of all serum and intrahepatic virological markers to levels below the detection limit. A14 CAR T cells treatment increased the levels of human IFN-γ, GM-CSF, and IL-8/CXCL-8 in the mice. These results show that A14 CAR T cells may be further developed for curative therapy against HBV infection by eliminating HBV-infected hepatocytes and inducing production of pro-inflammatory and antiviral cytokines.

Decision curve analysis to identify optimal candidates of liver resection for intermediate-stage hepatocellular carcinoma with hepatitis B cirrhosis: A cohort study.

The selection criterion for liver resection (LR) in intermediate-stage (IM) hepatocellular carcinoma (HCC) is still controversial. This study aims to compare LR and transarterial chemoembolization (TACE) in the range of predicted death risk The multivariable Cox regression model (MVR) was estimated to predict mortality at 5 year. The cutoff values were determined by a 2-piece-wise linear regression model, decision curve analysis with MVR model, and hazard ratio curve for treatment plotted against the predicted mortality. 825 IM-hepatocellular carcinoma (IM-HCC) with hepatitis B cirrhosis were included for analysis (TACE, n = 622; LR, n = 203). The 5-year overall survival (OS) rate of LR patients was higher than the TACE group (52.8% vs 20.8%; P < .0001). The line of LR and TACE were crossing with predicted death risk at 100% (P for interaction = .008). The benefit of LR versus TACE decreased progressively as predicted death risk > 0.55 (95%CI: 0.45, 0.62). When predicted death risk over 0.7, decision curve analysis suggested that LR and TACE did not increase net benefit. Patients were then divided into 4 subgroups by the cutoff values (<0.45, 0.45≥/<0.62, 0.62≥/<0.7, ≥0.7). The stratified analysis of treatment in different subgroups, hazard ratios were 0.39 (95%CI: 0.27, 0.56), 0.36 (95%CI: 0.23, 0.56), 0.51 (95%CI: 0.27, 0.98), and 0.46 (95%CI: 0.27, 0.80), respectively. LR reached the maximal relative utility in the interval of 0.45 to 0.62, and both LR and TACE did not increase net benefit at the 5-year death risk over 0.7.

Inhibition of nonhomologous end joining-mediated DNA repair enhances anti-HBV CRISPR therapy.

Current anti-hepatitis B virus (HBV) therapies have little effect on covalently closed circular DNA (cccDNA) and fail to eliminate HBV. The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system has been reported to directly target cccDNA and exert antiviral effects. In this study, we hypothesized that the inhibition of the DNA repair machinery, which is important for the repair of CRISPR-induced double-strand breaks, may enhance the effect of CRISPR targeting cccDNA, and we investigated the antiviral effect of potential combination therapy. The antiviral effect of CRISPR targeting cccDNA (HBV-CRISPR) was evaluated in HBV-susceptible HepG2-hNTCP-C4 cells expressing Cas9 (HepG2-hNTCP-C4-iCas9) or primary human hepatocytes (PHHs) expressing Cas9. Following HBV infection, HBV-CRISPR reduced cccDNA levels, accompanied by decreases in pregenomic RNA (pgRNA) levels and supernatant HBV DNA, hepatitis B surface antigen and hepatitis B e antigen levels in HepG2-hNTCP-C4-iCas9 cells, and PHHs. HBV-CRISPR induced indel formation in cccDNA and up-regulated poly(adenosine diphosphate ribose) polymerase (PARP) activity in HBV-infected HepG2-hNTCP-C4-iCas9 cells. The suppression of PARP2-Histone PARylation factor 1 (HPF1) (involved in the initial step of DNA repair) with small interfering RNA (siRNA) targeting either PARP2 or HPF1 increased the reduction in pgRNA and cccDNA by HBV-CRISPR in HBV-infected HepG2-hNTCP-C4-iCas9 cells. The suppression of DNA Ligase 4 (LIG4) (essential for nonhomologous end joining [NHEJ]) but not breast cancer susceptibility gene (BRCA) (essential for homologous recombination) enhanced the antiviral effect of HBV-CRISPR in HBV-infected HepG2-hNTCP-C4-iCas9 cells. Finally, the clinically available PARP inhibitor olaparib increased the reductions in pgRNA and cccDNA levels induced by HBV-CRISPR in HBV-infected HepG2-hNTCP-C4-iCas9 cells and PHHs. Conclusion: The suppression of the NHEJ-mediated DNA repair machinery enhances the effect of CRISPR targeting cccDNA. The combination of CRISPR and olaparib may represent a therapy for HBV elimination.

Targeting the hepatitis B cccDNA with a sequence-specific ARCUS nuclease to eliminate hepatitis B virus in vivo.

Persistence of chronic hepatitis B (CHB) is attributed to maintenance of the intrahepatic pool of the viral covalently closed circular DNA (cccDNA), which serves as the transcriptional template for all viral gene products required for replication. Current nucleos(t)ide therapies for CHB prevent virus production and spread but have no direct impact on cccDNA or expression of viral genes. We describe a potential curative approach using a highly specific engineered ARCUS nuclease (ARCUS-POL) targeting the hepatitis B virus (HBV) genome. Transient ARCUS-POL expression in HBV-infected primary human hepatocytes produced substantial reductions in both cccDNA and hepatitis B surface antigen (HBsAg). To evaluate ARCUS-POL in vivo, we developed episomal adeno-associated virus (AAV) mouse and non-human primate (NHP) models containing a portion of the HBV genome serving as a surrogate for cccDNA. Clinically relevant delivery was achieved through systemic administration of lipid nanoparticles containing ARCUS-POL mRNA. In both mouse and NHP, we observed a significant decrease in total AAV copy number and high on-target indel frequency. In the case of the mouse model, which supports HBsAg expression, circulating surface antigen was durably reduced by 96%. Together, these data support a gene-editing approach for elimination of cccDNA toward an HBV cure.

Therapeutic potentials of CRISPR-Cas genome editing technology in human viral infections.

Viral infections are a common cause of morbidity worldwide. The emergence of Coronavirus Disease 2019 (COVID-19) has led to more attention to viral infections and finding novel therapeutics. The CRISPR-Cas9 system has been recently proposed as a potential therapeutic tool for the treatment of viral diseases. Here, we review the research progress in the use of CRISPR-Cas technology for treating viral infections, as well as the strategies for improving the delivery of this gene-editing tool in vivo. Key challenges that hinder the widespread clinical application of CRISPR-Cas9 technology are also discussed, and several possible directions for future research are proposed.

The viral hepatitis B care cascade: A population-based comparison of immigrant groups.

BACKGROUND AND AIMS: The global burden of viral hepatitis B is substantial, and monitoring infections across the care cascade is important for elimination efforts. There is little information on care disparities by immigration status, and we aimed to quantify disease burden among immigrant subgroups. APPROACH AND RESULTS: In this population-based, retrospective cohort study, we used linked laboratory and health administrative records to describe the HBV care cascade in five distinct stages: (1) lifetime prevalence; (2) diagnosis; (3) engagement with care; (4) treatment initiation; and (5) treatment continuation. Infections were identified based on at least one reactive antigen or nucleic acid test, and lifetime prevalence was estimated as the sum of diagnosed and estimated undiagnosed cases. Care cascades were compared between long-term residents and immigrant groups, including subgroups born in hepatitis B endemic countries. Stratified analyses and multivariable Poisson regression were used to identify drivers for cascade progression. Between January 1997 and December 2014, 2,014,470 persons were included, 50,475 with infections, of whom 30,118 were engaged with care, 11,450 initiated treatment, and 6554 continued treatment >1 year. Lifetime prevalence was estimated as 163,309 (1.34%) overall, 115,722 (3.42%) among all immigrants, and 50,876 (9.37%) among those from highly endemic countries. Compared to long-term residents, immigrants were more likely to be diagnosed (adjusted rate ratio [aRR], 4.55; 95% CI, 4.46, 4.63), engaged with care (aRR, 1.07; 95% CI, 1.04, 1.09), and initiate treatment (aRR, 1.09; 95% CI, 1.03, 1.16). CONCLUSIONS: In conclusion, immigrants fared well compared to long-term residents along the care cascade, having higher rates of diagnosis and slightly better measures in subsequent cascade stages, although intensified screening efforts and better strategies to facilitate linkage to care are still needed.

Hepatitis B virus envelope proteins can serve as therapeutic targets embedded in the host cell plasma membrane.

Hepatitis B virus (HBV) infection is a major health threat causing 880,000 deaths each year. Available therapies control viral replication but do not cure HBV, leaving patients at risk to develop hepatocellular carcinoma. Here, we show that HBV envelope proteins (HBs)-besides their integration into endosomal membranes-become embedded in the plasma membrane where they can be targeted by redirected T-cells. HBs was detected on the surface of HBV-infected cells, in livers of mice replicating HBV and in HBV-induced hepatocellular carcinoma. Staining with HBs-specific recombinant antibody MoMab recognising a conformational epitope indicated that membrane-associated HBs remains correctly folded in HBV-replicating cells in cell culture and in livers of HBV-transgenic mice in vivo. MoMab coated onto superparamagnetic iron oxide nanoparticles allowed to detect membrane-associated HBs after HBV infection by electron microscopy in distinct stretches of the hepatocyte plasma membrane. Last but not least, we demonstrate that HBs located on the cell surface allow therapeutic targeting of HBV-positive cells by T-cells either engrafted with a chimeric antigen receptor or redirected by bispecific, T-cell engager antibodies. TAKE AWAYS: HBs become translocated to the plasma membrane. Novel, recombinant antibody confirmed proper conformation of HBs on the membrane. HBs provide an interesting target by T-cell-based, potentially curative therapies.

Treatments for HBV: A Glimpse into the Future.

The hepatitis B virus is responsible for most of the chronic liver disease and liver cancer worldwide. As actual therapeutic strategies have had little success in eradicating the virus from hepatocytes, and as lifelong treatment is often required, new drugs targeting the various phases of the hepatitis B virus (HBV) lifecycle are currently under investigation. In this review, we provide an overview of potential future treatments for HBV.

Challenges in the Application of Glyco-Technology to Hepatitis B Virus Therapy and Diagnosis.

Hepatitis B virus (HBV) is a major pathogen that causes acute/chronic hepatitis. Continuous HBV infection can lead to the development of hepatocellular carcinoma (HCC). Although several different anti-HBV treatments are available for chronic hepatitis B patients, discontinuing these medications is difficult. Patients with chronic hepatitis B at high risk for HCC therefore require close observation. However, no suitable biomarkers for detecting high-risk groups for HCC exist, except for serum HBV-DNA, but a number of HCC biomarkers are used clinically, such as alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (PIVKA-II). Glycosylation is an important post-translational protein modification involved in many human pathologic conditions. HBV surface proteins contain various oligosaccharides, and several reports have described their biological functions. Inhibition of HBV glycosylation represents a potential novel anti-HBV therapy. It is thought that glycosylation of hepatocytes/hepatoma cells is also important for HBV infection, as it prevents HBV from infecting cells other than hepatocytes, even if the cells express the HBV receptor. In this review, we summarize considerable research regarding the relationship between HBV and glycosylation as it relates to the development of novel diagnostic tests and therapies for HBV.

Risk of HBV Reactivation in Patients With Resolved HBV Infection Receiving Anti-CD19 Chimeric Antigen Receptor T Cell Therapy Without Antiviral Prophylaxis.

Background: Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel treatment modality for hematologic malignancies and is predicted to experience widespread use in the near future. However, not all risks associated with this novel approach are well defined. There are few data in the risk of HBV reactivation and limited experience in management in patients with resolved HBV infection who undergo CAR-T cell therapy. Methods: We performed a post-hoc analysis of a prospective clinical trial of anti-CD19 CAR-T (CART19) cell therapy in patients with relapsed or refractory (r/r) B-cell malignancies, and aimed at exploring the actual risk of HBV reactivation in a cohort of patients with resolved HBV infection receiving CART19 cell therapy in the absence of antiviral prophylaxis. Results: In this study, we investigated the risk of HBV reactivation after CART19 cell therapy in 30 consecutive patients with B-cell malignancies and resolved HBV infection without antiviral prophylaxis, in the Tongji Hospital of Tongji University. In this cohort, two patients developed HBV reactivation 2 months and 14 months after CAR-T cell infusion, respectively, the latter of whom developed severe hepatitis. These findings showed that the incidence of HBV reactivation was 6.67% (95% CI, 0.8-22.1). Specifically, none of the 21 patients who were HBsAb positive (0.0%) versus two of nine patients who were HBsAb negative (22.2%) experienced HBV reactivation (p = 0.03), suggesting HbsAb seronegativity at baseline is a possible risk factor in this population. Although use of tocilizumab or corticosteroids has been associated with increased risk of HBV reactivation, none of the patients who received these agents had HBV reactivation in this study. Conclusion: This is the first and largest study to assess the true incidence of HBV reactivation in patients with resolved HBV infection receiving CART19 cell therapy without antiviral prophylaxis. This study highlights that this population are at risk of developing HBV reactivation and indicates that close monitoring of HBV DNA is required in the absence of antiviral prophylaxis. In addition, antiviral prophylaxis is recommended in the HBsAb-negative subpopulation.

Calcium signaling in hepatitis B virus infection and its potential as a therapeutic target.

As a ubiquitous second messenger, calcium (Ca2+) can interact with numerous cellular proteins to regulate multiple physiological processes and participate in a variety of diseases, including hepatitis B virus (HBV) infection, which is a major cause of hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. In recent years, several studies have demonstrated that depends on the distinct Ca2+ channels on the plasma membrane, endoplasmic reticulum, as well as mitochondria, HBV can elevate cytosolic Ca2+ levels. Moreover, within HBV-infected cells, the activation of intracellular Ca2+ signaling contributes to viral replication via multiple molecular mechanisms. Besides, the available evidence indicates that targeting Ca2+ signaling by suitable pharmaceuticals is a potent approach for the treatment of HBV infection. In the present review, we summarized the molecular mechanisms related to the elevation of Ca2+ signaling induced by HBV to modulate viral propagation and the recent advances in Ca2+ signaling as a potential therapeutic target for HBV infection. Video Abstract.

Human immune repertoire in hepatitis B virus infection.

Hepatitis B virus (HBV) infection is a public health threat that affects 257 million people worldwide and can progress to liver cirrhosis, liver failure, and hepatocellular carcinoma. The HBV antigen- induced adaptive immune response plays an important role in HBV clearance. Immune repertoire sequencing (IRS) has been used to investigate the molecular mechanisms behind the immune system, find novel ways to treat HBV infection, and evaluate the genetic responses and immune characteristics of individuals infected by HBV or immunized by HBV vaccine. This review summarizes the human immune repertoire analysis methodology, and the application of the IRS in the prediction of HBV infection progression, treatment, and vaccination.

Thermal-triggered packing of lipophilic NIR dye IR780 in hepatitis B core at critical ionic strength and cargo-host ratio for improved stability and enhanced cancer phototherapy.

Virus-like particles (VLPs) holding internal cavity with diameter from tens up to one hundred nanometers are attractive platform for drug delivery. Nevertheless, the packing of drugs in the nanocage mainly relies on complicated disassembly-reassembly process. In this study, hepatitis B core protein (HBc) VLPs which can withstand temperature up to 90 °C was employed as carrier to load a lipophilic near infrared dye IR780. It was found that an attaching-dis-atching-diffusing process was involved for the entering of IR780 in the cavity of HBc. The first two steps were associated with the electrostatic interactions between oppositely charged HBc and IR780, which was critically manipulated by ionic strength and HBc/IR780 mass ratio at which they were mixed; while the diffusion of IR780 across the shell of HBc showed a temperature-dependent manner that can be triggered by thermal induced pore-opening of the HBc capsid. At optimized condition, about 1055 IR780 molecules were encapsulated in each HBc by simply mixing them for 10 min at 60 °C. Compared with free IR780, the HBc-IR780 particles showed significantly improved aqueous and photostability, as well as enhanced photothermal and photodynamic performance for cancer therapy. This study provides a novel drug loading strategy and nanomemedicine for cancer phototherapies.

What Is the Risk of Reactivation in Patients with Resolved and Past HBV Infection During Immunosuppressive Therapy If HBV-DNA Negative before Treatment?

BACKGROUND: Reactivation of Hepatitis B (HBVr) related to immunosuppressive drug therapy (ISDT) in patients with resolved and past infection is a challenging entity. The number of prospective long-term studies is limited. METHODS: Two groups of patients with resolved and past HBV infection were analyzed prospectively. The patients were further categorized as 266 patients receiving ISDT (group 1) and 246 patients receiving antineoplastic therapy (group 2). RESULTS: We did not detect any cases of HBVr among 108 patients receiving rituximab (71 of which were anti-HBc positive only), 111 patients receiving tumor necrosis factor inhibitors (66 of which were anti-HBc positive only), and 42 patients receiving high-dose glucocorticoids for more than 4 weeks (24 of which were anti-HBc positive only) during a mean follow-up time of more than 24 months. Subgroup analysis of the anti-HBs (+) patients showed that in group A (anti-HBs >1000 mIU/mL) the antibody levels did not change; in group B (anti-HBs between 100 and 1000 mIU/mL) the antibody levels changed non-significantly (P = .25), and in Group C (anti-HBs between 0 and 100 mIU/mL) the antibody levels declined significantly (P = .002). Furthermore, 16 patients in Group C had an anti-HBs loss during follow-up, but no HBVr was detected. CONCLUSION: The risk of HBVr by immunosuppressive therapy in this group may be lower than that suspected in the literature and anti- HBs levels may not seem to correlate with the risk of reactivation.

Cuban Prophylactic and Therapeutic Vaccines for Controlling Hepatitis B.

Hepatitis B causes liver failure, cirrhosis and cancer. It has an estimated global prevalence of 6%, and 700,000 to 1 million persons die every year of hepatitis B-related causes. In 1989, hepatitis B incidence in Cuba was 14.9 per 100,000 population. To control infection, the Genetic Engineering and Biotechnology Center and the Ministry of Public Health, both in Havana, collaborated on a joint project that first produced natural interferon and recombinant interferon alpha-2b, and later a polyethylene glycolconjugated interferon. As part of the Cuban biotechnology development strategy, the project produced a vaccine against hepatitis B in 1985. At that time, hepatitis B vaccines available elsewhere in the world were costly and inaccessible to Cubans due to the US economic and trade embargo. The Heberbiovac HB preventive vaccine was approved by the Cuban regulatory authority and added to the Cuban newborn vaccination program in 1992 after phase 1-3 clinical trials demonstrated its safety and immunogenicity. From 2001 to 2003, PAHO/WHO qualified and requalified the vaccine four times. When associated with other antigens or molecules, Heberbiovac HB provides a common platform of virus-like particles that can be used in different ways, such as in the pentavalent vaccine containing Bordetella pertussis and Haemophilus infl uenzae type b antigens and tetanus and diptheria toxoids. Thanks to this vaccine, annual incidence of acute hepatitis in Cuba has dropped from more than 2000 cases to fewer than 100, and no infections in children aged 0-15 years have been reported since 2007. It is now used in more than 30 countries, providing protective, long-lasting antibody levels with no reports of serious adverse events. Yet, hepatitis B cannot be eliminated until there are no chronic patients. The comprehensive hepatitis B control project therefore included development of a therapeutic vaccine based on Heberbiovac HB. Using its platform, researchers designed an innovative version of the vaccine that was the precursor of a therapeutic nasal/subcutaneous vaccine for chronic hepatitis B, HeberNasvac. This precursor vaccine, which combines Heberbiovac HB with a recombinant antigen from the virus nucleocapsid (rHBcAg), was patented and licensed in 2015 by the Cuban regulatory authority. This article provides an overview of the progress-to-date on the development of this therapeutic vaccine, including clinical trials (some completed and others ongoing) to determine safety, efficacy and therapeutic benefits.