| The hepatitis B virus (HBV) infection is a major infectious disease that seriouslythreatened the health of our people, and it is the main reason for chronic hepatitis, cirrhosisand liver cancer. The therapy of Chronic hepatitis B is very difficult, and no drug treatmentcan make it be healed. With regard to the treatment of chronic hepatitis B, antiviral treatmentis the key. There are two main ways to treat CHB, one is by stimulating the immune, such asinterferon (IFN), the other is by inhibiting replication of HBV, taking orally antiviral drugs:nucleoside (acid) analogues. Interferon can effectively suppress replication of HBV,and thusvia stimulating the immune system to induce liver disease's mitigation. Nevertheless,thelimited efficacy,flu-like adverse reactions and relatively strict indications, contraindicationslimit its clinical application. Nucleoside (acid) analogues has the feature that tolerance,security, and be easy to take and so on, it has been widely used in clinical anti-HBV therapy.But its drawback is that the long-term medication prone to viral resistance, viral reboundafter resistance mutations will offset the pre-clinical benefit, and thus, to seek more potentinhibition of viral replication, low resistance and long-term safety of the drug is focus ofdrug research. A new nucleoside (acid) analogues of antiviral drug-tenofovir disoproxilfumarate (TDF) has brought new hope to patients, to date, there is no clinical resistancereport in HBV of TDF. TDF has not yet been approved for marketing in our country, and isnow in clinical trials. Host factors play an important role in the process of Chronic HBVinfection and therapy. Inflammatory cytokines TNF-α, IFN-γ, IL-2, IL-4, IL-6, IL-10andIL-17A play important roles in this process. In recent years, with the development ofgenomics research, we find that single nucleotide polymorphism(SNP) of the host also playan important role in HBV infection and removal.But,immunology research related to HBVinfectIino nth iiss nsotut dcyle,awre. collected outpatients and hospitalized patients with CHB of the FirstHospital of Jilin University,and began screening test after signing informed consent,weselected24previously untreated patients with CHB that giving them nucleoside andnucleotide analogues, including HBeAg-positive or-negative cases (HBVDNA in≥105copies/ml, an interval of14days or more than twice elevated ALT of HBeAg positivepatients≥2ULN(upper limit of normal); HBeAg-negative patients>1ULN and≤10ULN),used randomized, double-blind, double-dummy, active drug controlled study, randomly divided into tenofovir disoproxil fumarate300mg/d treatment group, or adefovirdipivoxil10mg/d treatment one according to1:1, and detected liver function, hepatitis Bvirus markers and HBV DNA quantitative in the treatment of baseline and after4weeks,8weeks,12weeks,24weeks treatment; Compared the response of biochemical andvirological and cytokines in the dynamic changes after treatment, analyzed theirrelevance;Simultaneously determined IL-10SNPs (rs1800896, rs1800871, rs1800872) of the24patients, and analyzed the relevance with antiviral treatment and the dynamic changes ofcytokines.In this study, we used three-color method of flow cytometry,and adopted the method ofmicro-array flow cytometry (CBA) and pyrosequencing technology to do the followingwork:(1)Observe the response of biochemical and virological for the treatment of chronichepatitis B patients with tenofovir disoproxil fumarate after4weeks,8weeks,12weeks, andcompared with adefovir dipivoxil.(2) Dynamicly observed the serum concentrations of cytokines for the treatment ofchronic hepatitis B patients with tenofovir disoproxil fumarate after4weeks,8weeks,12weeks,24weeks, including the cytokines TNF-α,IFN-γ, IL-2, IL-4, IL-6, IL-10and IL-17A,to analyze the variation; and compared with adefovir dipivoxil.(3)In the chronic hepatitis B patients with tenofovir disoproxil and adefovir dipivoxiltreatment, human IL-10SNPs (rs1800896, rs1800871, rs1800872) loci were detected, toanalyzed the correlation of IL-10SNPs and the antiviral efficacy and the relationshipbetween IL-10SNPs and cytokine changes.The results are as follows:(1) In patients with chronic hepatitis B with tenofovir disoproxil treatment, ALT, ASTand HBV DNA were markedly improved, and HBV DNA quantity decreased dramaticallyfrom baseline in4weeks,8weeks,12weeks,24weeks treatment(P <0.05).Significant differences of the levels of HBV DNA exists between0weeks and12weeks,0weeks and24weeks (p <0.05).The above indicators in tenofovir disoproxil treatmentgroup compared with the adefovir dipivoxil group have the same changing tendency.In sevenHBeAg positive patients with24weeks treatment of tenofovir disoproxil, three casesachieve HBeAg seroconversion. However, no HBeAg seroconversion occurred in8patientswith adefovir dipivoxil treatment. (2) In the chronic hepatitis B patients with tenofovir disoproxil treatment, thedeclination of serum IL-10levels in12weeks,24weeks compared with baseline is statisticalsignificance (p <0.05). The similar significant changes exist between4weeks and12weeks,8weeks and12weeks,12weeks and24weeks(p <0.05).Serum IL-10levels are negativelyrelated with the declination of HBV DNA quantity(p <0.05).After24weeks treatment, thelevel of IL-17A in serum decreased clearly compared with the baseline(p <0.05).The levelsof IFN-γ and TNF-α, IL-2, IL-4, IL-6in serum showed no obviously change in the processof treatment. For the other hand, in the patients of chronic hepatitis B with adefovir dipivoxiltreatment,the same declination occurred as the tenofovir disoproxil treatment group; theother six cytokines showed no significant change.(3) IL-10SNPs(rs1800896,rs1800871,rs1800872)have little correlation with theantiviral efficacies of the two kinds of medicine,as well as the levels of IL-10,IL-17A(p＞0.05).Changes of the cytokines level in the tenofovir disoproxil antiviral treatment processsuggest that immunomodulatory may play a role in the inhibition of viral after using themedicine. Virological response analysis showed the association between the levels of serumcytokines IL-10and HBVDNA.Thus, it is considered that the levels of IL-10in serum areclosely related to the viral replication in the process of tenofovir disoproxil therapy. Thelevels of IL-10, IL-17A can be used as clinical indicators for monitoring the course of theearly stages of the treatment, to evaluate prognosis and the disease outcome in patients withchronic hepatitis B.The fluctuation of cytokines secreted by Th1/Th2/Th17cells were obtained by dynamicmonitoring of the chronic hepatitis B patients with antiviral treatment, which is significant toelucidate the pathogenesis of chronic hepatitis B and to guide clinical treatment. |
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