Progress in treatment of anti-hepatitis B virus drug nucleoside analogues in preventing mother-to-child transmission / 中国药理学通报

Mother-to-child transmission of hepatitis B virus (HBV) is one of the main ways of transmission and the main cause of chronic hepatitis B after infection. Therefore, preventing mother-to-child transmission of HBV is particularly important in reducing the incidence of chronic hepatitis B. Currently, nucleoside ( acid) analoids ( Nas ) used for mother-to-child blocking of HBV include lamivudine (LAM) , tibivudine (LdT) and tenofovir fumarate ( TDF). Propofol tenofovir fumarate (TAF) has also been used in pregnant chronic hepatitis B pa- tients. This paper summarizes the efficacy, safety and antiviral treatment indications and termination time of the above-mentioned drugs in mother-to-child preventing to provide suggestions for the selection and rational application of mother-to-child preventing Nas.

Establishment and application of hepatic organoid model of hepatitis B virus infection / 中华传染病杂志

Objective:To establish the hepatic organoid of hepatitis B virus (HBV) infection on the basis of induced pluripotent stem cells (iPSC) and an inverted colloidal crystal polyethylene glycol scaffold (ICC), and to evaluate the antiviral effect of nucleoside drugs.Methods:iPSC was differentiated into hepatocyte-like cells (HLC), and inoculated into ICC to construct a hepatic organoid. The relative mRNA expressions of Nanog homeobox (NANOG), sex determining region Y-box (SOX) 2, SOX17, forkhead box protein A2 (FOXA2), alpha fetoprotein (AFP) and albumin (ALB) were detected by real time quantitative polymerase chain reaction (RT-qPCR). Confocal laser microscopy was used to photograph the three-dimension (3D) structure of organs. The expression of sodium taurocholate cotransporting polypeptide (NTCP) in HLC was analyzed by Western blot and immunofluorescence. HepG2.2.15 cells were used to extract HBV virus particles to infect hepatic organoid. The relative expression of HBV pregenome RNA (pgRNA) in cells was detected by RT-qPCR. The expressions of hepatitis B core antigen (HBcAg) and hepatitis B surface antigen (HBsAg) in cytoplasm were observed under confocal laser microscopy. A total of 0.5 μmol/L entecavir and 0.5 μmol/L lamivudine were used to treat the infected cells respectively. The relative expression of HBV pgRNA in infected and uninfected cells was detected by RT-qPCR. Independent sample t test and one-way analysis of variance were used for statistical analysis. Results:Within 21 days of iPSC differentiation, the mRNA expressions of NANOG and SOX2 in stem cells markers decreased ( F=158.90 and 8.31, respectivley; P<0.001 and P=0.002, respectively), while the mRNA expressions of SOX17 and FOXA2 in the endoderm increased first and then decreased ( F=37.23 and 82.57, respectively, both P<0.001). In the later stage of differentiation, the mRNA expressions of AFP and ALB in liver cells increased ( F=4.65 and 34.64, respectively, P=0.012 and P<0.001, respectively), and all differences were statistically significant. NTCP was highly expressed in differentiated cells detected by Western blot and fluorescence microscopy, the protein expression level was 0.803±0.099. Confocal laser microscopy confirmed that the differentiated cells expressed ALB and presented spherical structure in ICC. The expression of HBV pgRNA and the immunostaining of HBsAg and HBcAg confirmed that HBV successfully infected hepatic organoid. Three days after the application of entecavir and lamivudine, the HBV pgRNA level decreased significantly both in entecavir group (0.665±0.220) and lamivudine group (0.503±0.117) compared to the uninfected cells (3.347±0.454), and the differences were both statistically significant ( t=10.53 and 12.72, respectively, both P<0.001). Conclusions:HLC display hepatic specific genes ALB and NTCP. Hepatic organoids constructed with iPSC and ICC have human liver function and can be infected by HBV. Entecavir and lamivudine could effectively inhibit the replication of HBV in hepatic organoids.

Discontinuation of nucleoside/nucleoside analogues therapy in compensated patients with hepatitis B cirrhosis after HBsAg negative conversion / 中华临床感染病杂志

Objective:To evaluate the safety of discontinuing nucleoside/nucleoside analogue (NAs) therapy in patients with compensated hepatitis B cirrhosis after HBsAg negative conversion.Methods:A total of 3 783 patients with hepatitis B cirrhosis in compensated stage were treated with NAs at Taizhou Hospital, Taizhou Municipal Hospital and Taizhou Enze Hospital from January 2008 to December 2020. The clinical data and laboratory tests results of 85 patients with HBsAg negative conversion were retrospectively analyzed, including 36 cases discontinued the drug, and 49 continued to use drug. Chi-square test and rank-sum test were used for data analysis.Results:During the 24 and 48 months of follow-up, the ALT levels were within the normal range in both groups. There were no significant differences in positive rates of anti-HBs and HBeAg ( χ2=0.75, 0.39 and 0.90, P=0.78 0.84 and 0.34; χ2=0.40, 0.00 and 0.00, P=0.84, 1.00 and 1.00) between two groups. After 48 months of follow-up, 2 cases of primary liver cancer occurred in the discontinuation group and no primary liver cancer occurred in the continuation group ( χ2=0.89, P=0.34). Throughout the follow-up, HBsAg remained negative and HBV DNA load was below the lower limit of detection in both groups. Conclusions:Discontinuation of NAs can be considered after the HBsAg negative conversion in patients with compensated hepatitis B cirrhosis.

Role of the stability of deoxyribonucleoside triphosphate pool in the development and progression of tumors / 肿瘤研究与临床

The stability of deoxyribonucleoside triphosphate (dNTP) pool is essential for the normal synthesis of nuclear and mitochondrial DNA. The lack or excess of any dNTP may cause DNA damage and genomic instability, and increase mutation rate. Present studies have confirmed that the instability of dNTP pool is closely related to a variety of tumorigenesis. In addition, dNTP pool is involved in the development of tumor via multiple pathways, while the mechanisms of tumors caused by the instability of dNTP are complicated. This paper discusses the relationship between the stability of dNTP pool and DNA damage repair to provide a theoretical basis for early diagnosis and targeted treatment of tumors.

Efficacy of nucleoside analogues antiviral therapy on clinical outcome for HBV-related primary hepatic carcinoma patients after hepatectomy / 实用医学杂志

Objective To evaluate the efficacy of nucleoside analogues (NAs) antiviral therapy on clinical outcome for hepatitis B virus (HBV)-related primary hepatic carcinoma patients after hepatectomy. Methods The clinical data of 156 HBV-related primary hepatic carcinoma patients after hepatectomy were retrospectively analyzed..According to whether accepted postoperative antiviral treatment, all patients were divided into control group (n = 80)and observation group (n = 76). The serum HBV DNA capacity, recurrence-free survival (RFS)and overall survival (OS)were compared between two groups. Results One week, 1 month, 2 months and 3 months after operation , the serum HBV DNA capacity of observation group was significantly lower than that of control group(P < 0.05). One year, 3 years and 5 years after operation, intergroup comparison of RFS rate of both groups showed statistical significance (P < 0.05) and 1 year, 3 years and 5 years after operation, the difference of OS rate of both groups indicated statistical significance (P < 0.05). Conclusion Standard NAs antiviral treatment for HBV-related primary hepatic carcinoma patients after hepatectomy ,can improve prognosis and prolong survival time. The inhibition the HBV copy active may be its mechanism.

High-dose tenofovir is not effective in suppressing hepatitis B virus replication in patients with hepatocellular carcinoma progression: a preliminary result

BACKGROUNDS/AIMS: Nucleos(t)ide analogues (NUCs) effectively suppress hepatitis B virus (HBV) replication, but hepatocellular carcinoma (HCC) recurrence often leads to HBV replication despite NUC therapy. The aim of this study was to determine whether high-dose tenofovir (TNF) therapy can suppresses HCC recurrence-associated HBV replication. METHODS: We performed a single-arm prospective study to assess the clinical feasibility of high-dose TNF (hdTNF). We recruited 10 patients during September 2015 and followed up for 3 months or early drop-out. RESULTS: All 10 patients had HCC of advanced stages due to HCC recurrence and gradual progression. The average age of patients was 51.2+/-4.7 years and 9 were male. Three patients did not tolerate the increased TNF dosage and were dropped out early. The other 7 patients were relatively tolerable to the increased dosage of TNF 5 tablets per day. One patient had mild gastrointestinal symptoms and another patient complained of insomnia. Increased HBV replication and HCC progression was observed despite hdTNF for 4-8 weeks. All 7 patients showed tumor progression during the 3 month follow-up. In these patients, blood HBV DNA before hdTNF was 50-200 copies/ml; and 4-8 weeks after hdTNF, the HBV replication status was not improved with blood HBV DNA of 50-300 copies/ml. This clinical study was terminated early after these negative results were confirmed. CONCLUSIONS: The results of this study indicated that high dose of TNF up to 5-fold the recommended dosage is not tolerated by a considerable proportion of patients and also ineffective in suppressing HCC progression-associated HBV replication.

Study on the effect of liver function and tumor marker of patients with liver cirrhosis after hepatitis B by nucleoside drugs Entecavir / 中国生化药物杂志

Objective To investigate the effects of liver function and tumor markers by nucleoside analogues Entecavir on patients with liver cirrhosis after hepatitis B.Methods 90 patients with liver cirrhosis after hepatitis B were selected, according to the different drugs were divided into experimental group and control group.Liver function and levels of tumor markers were compared after experiment.Results Two groups of patients with male to female ratio, average age, course of disease, no significant difference in general data of hepatitis B virus DNA content, comparable (P>0.05);Compared with the control group, the experimental group HBV DNA level is low, the negative rate was significantly higher (P<0.05);Compared with the control group, the experimental group ALT, AST and TBiL levels were significantly increased(P<0.05), ChE, AlB were significantly decreased (P<0.05);Compared with the control group, the experimental group CEA, AFP, CA125 and lower CA199 levels (P<0.05).Conclusion Nucleoside drugs can significantly improve liver function in patients with liver cirrhosis after hepatitis Band tumor markers indicators, and it is significance for treatment of liver cirrhosis after hepatitis.

Progress in study of antiviral effect of chronic hepatitis B / 药学实践杂志

Chronic hepatitis B is a worldwide infectious diseases caused by hepatitis B virus (HBV) .HBV infection is an important reason for liver cirrhosis and liver cancer in our country .Currently ,the interferon and nucleoside analogs antiviral drugs (nucleotides) is widely used in clinical practice .These drugs inhibit the replication of the virus and disease development to a certain extent ,but not fundamentally eliminate the virus .Various therapeutic vaccines have also made certain curative effect in anti HBV ,but the effect is not perfect clinically .At present ,many research results demonstrate that biological immu-notherapy can successfully eliminate HBV virus in the body , therefore it has brought a new hope for the treatment of hepatitis B .

Successful treatment of B cell prolymphocytic leukemia by fludarabine, cyclophosphomide and rituximab therapy: own experience and literature review / 白血病·淋巴瘤

Objective To explore the clinical characteristics of B cell prolymphocytic leukemia (B-PLL).Methods The clinical manifestation,treatment and outcome of a 33-year-old man with B-PLL were reported.Results The young patient had thrombocytopenia and systemic B-symptoms,markedly raised lymphocyte'count,bulky splenomegaly and lymphadenopathy.He refused stem cell transplant,so RFC regimen (fludarabine,cyclophosphomide and rituximab) therapy were administered.After 4 cycles of RFC therapy,the patient achieved a complete immunophenotypical and hematological remission response.Conclusion RFC therapy might be a feasible and useful treatment option for B-PLL.

Nucleoside analogues against hepatitis B virus: Research advances / 国际药学研究杂志

Hepatitis B virus is a serious hazard to human health, and the research and development of anti-hepatitis B virus drugs have become hot topics in the world. Based on the literature at home and abroad, the recent progress of anti-hepatitis B virus agents is reviewed in this paper, including structure characteristics, antiviral mechanism, in vitro and in vivo activity evaluation, and clinical application. Furthermore, the opportunities and challenges for anti-hepatitis B virus drugs in China are prospected.

Avanços no tratamento da hepatite pelo vírus B / Advances in the treatment of hepatitis B

Nos últimos anos, houve um grande progresso no tratamento da hepatite B crônica. Cinco drogas são hoje aprovadas para tratamento dessa virose: intérferon alfa, lamivudina, adefovir, entecavir e telbivudina. Os intérferons (convencionais ou peguilados) foram as primeiras drogas utilizadas no tratamento dessas infecções podendo levar a resposta sustentada (perda do DNA-VHB e do AgHbe) em até um terço dos casos tratados. Um grande número de análogos de nucleosídeos/nucleotídeos estão no momento, disponíveis para tratar a hepatite B; a eficácia da lamivudina, o primeiro análogo de nucleosídeo utilizado, é limitada pela elevada incidência de resistência. O adefovir tem eficácia comparável à lamivudina porém baixa freqüência de resistência. Entecavir e tenofovir também se mostram muito ativos em controlar a replicação do vírus da hepatite B, e estão associados com mínimo desenvolvimento de resistência, mesmo em tratamento prolongados. Outras drogas, tais como telbivudina, emtricitabina e clevudine, se tornarão em futuro próximo, novas armas no controle dessa virose. Co-infectados HIV/VHB representam um grupo de doentes de difícil manuseio e que hoje se beneficiam com combinações de drogas no esquema anti-retroviral potente que devem atuar em ambas as viroses. O desenvolvimento de antivirais mais potentes e novas associações de medicamentos, conjuntamente com a melhor compreensão dos mecanismos de resistência do vírus da hepatite B a terapia são importantes conquistas para melhorar a eficácia do tratamento e diminuir no futuro, a carga global de portadores do vírus da hepatite B.

Over the last years there has been considerable progress in the treatment of chronic hepatitis B. Five drugs are now approved for the treatment of this virosis: interferon alpha, lamivudine, adefovir, entecavir and telbivudine. Interferons (conventional or PEG) were the first medicine used in the treatment of hepatitis being able to lead the persistent response (loss of DNA-HBV and of AgHbe) to up to one third of treated cases. A large number of nucleoside/nucleotide analogues are, at present, available to treat hepatitis B. The efficacy of lamivudine, the first nucleoside analogue used, is limited by the high rate of resistance. Adefovir has efficacy comparable to that of lamivudine, but with low resistance rate. Entecavir and tenofovir have also been particularly active in the control of hepatitis B virus replication and are associated with minimal resistance development, even during long treatment regimens. Other drugs, such as telbivudine, emtricitabine and clevudine, will become new treatment options in the near future. Individuals co-infected with HIV/HBV are particularly difficult to manage and are nowadays able to benefit from combinations of drugs of the HAART therapy, which should be effective towards both viruses. The development of more potent antiviral drugs as well as new drug combinations, together with a better understanding of hepatitis B virus resistance mechanisms are important milestones to improve treatment efficacy and to diminish, in the future, the global burden of hepatitis B virus.

Evaluation of HBV drug-resistance in vitro and the molecular mechanism of resistance to nucleoside analogue therapy / 医学研究生学报

Nucleoside analogues are currently the main drug therapy against HBV infection. However, this type of therapy can cause gene mutations in HBV that result in drug resistance. The types of mutations caused by nucleoside analogues and the molecular mechanism of in vitro drug-resistance were reveiwed.

Molecular basis of activity of 8-azapurines in transcription processes.

The quantum mechanical perturbation method has been utilized to study the biological activity of 8-azapurine (8-azaguanosine, 8-azaadenosine and 8-aza-2,6-diaminopurine) nucleoside antibiotics. The in-plane (hydrogen bonding) and stacking energy of 8-azapurine bases have been evaluated with nucleic acid bases and base pairs in all possible orientations. The energy values and the sites of association of analogous bases, obtained by optimization of energy values as well as the sites of association of nucleic acid bases during the transcription process have been compared. The model developed earlier for the incorporation of nucleoside analogues has been used to find out the inhibitory effects of the drug on nucleic acid and protein synthesis. It has been observed that the activity of 8-azapurines are of the following order 8-azaguanine > 8-aza-2,6-diaminopurine > 8-azaadenine and these analogues show preference for binding near a guanine or cytosine in the chain. The results are in agreement with the experimental observations.

Interaction energy studies on pyrazolopyrimidine nucleoside antibiotics —A theoretical study: Oxoformycin Β.

The biological activity of oxoformycin Β has been exafned on the basis of the model developed for the incorporation of nucleoside analogues during transcription. Claverie's simplified formula has been employed for intermolecular interaction energy calculation. The pairing energy of oxoformycin Β base with complementary bases as well as the association energy with nucleic acid base pairs have been calculated. The results are compared with those of similar computation with normal bases. In addition to the in-plane interaction the vertical interaction energy between the analogue and the normal bases has been computed to specify the particular position of the analogue in the chain. On the basis of the model an attempt has been made to explain the mechanism of the biological action of oxoformycin Β and to compare the biological activity of pyrazolopyrimidine nucleoside analogues.