"有5人表面抗原转阴，" - 同意.
"其中有一人DNA复制降不下来" - (05B)不完全同意, 下降但不为0.
"8人中其中只有4个人治愈过" - 报告说3个人治愈.
"4个人中有1人复发且再用药物无效" - (02B) ?
"也就是说8人之中只有3人有效治愈。" - 同意.报告说相同:
three of these patients have achieved complete control of their infection after 20-27 weeks of treatment (HBV DNA -, HBsAg -, HBeAg -, anti-HBs +, anti-HBe +) and are being followed off treatment. These 3 patients are currently maintaining control over their infections 14, 27 and 52 weeks after stopping treatment.
这些患者中的三个都取得了完全控制其感染后20-27周的治疗（HBV - DNA - 乙肝表面抗原 - ，e抗原 - 抗- HBs，抗- HBe+），并正在遵循了治疗。这3例患者目前保持在控制他们的感染，14，27及52周停止治疗后，。 作者: StephenW 时间: 2011-9-5 14:07
"As the General Secretary of the Organizing Committee, I am pleased to inform you that Association for the Study of the Liver, Dhaka, Bangladesh (ASLDB) - the national Association of Hepatologists of the country, is going to organize the APASL 3rd STC on HBV Dhaka, Bangladesh from December 7 to, 2012. Your active participation is most vital in making this biggest even of Hepatology in Bangladesh a success and will surely go a long way in furthering Hepatology in this country.
On behalf of the Association members, I request your active participation in this meeting. Please mark the dates in your calender in advance, circulate this information among your friends and colleagues and encourage all to submit abstracts to the meeting.
We promise you some memorable times in Dhaka!
Dr. Mamun-Al-Mahtab (www.drmahtab.org)
Editor, LIVER: A Complete Book on Hepato-Pancreato-Biliary Diseases
Editor, Comprehensive Text Book of Hepatitis B
Secretary General, Association for the Study of the Liver, Dhaka, Bangladesh
Secretary General,Viral Hepatitis Foundation Bangladesh
Assistant Professor of Hepatology, Bangabandhu Sheikh Mujib Medical University
Deputy Editor-in-Chief, Euroasian Journal of Hepato-Gastroenterology
Deputy Editor-in-Chief, Clinical and Experimental Medical Journal
Editorial Board Member, Journal of Clinical and Experimental Hepatology
Journal of Global Infectious Diseases, Hepatitis Monthly, Microbiology Research
[attach]237190[/attach] 作者: hoimes 时间: 2011-9-5 19:41
Let assume that we have HbeAg negative, HbsAg suppress by Rep9Ac and DNA supress by antivirals. so, this is the best case for a chronic carrier (no e or s antigen for divert immune answer, no DNA means no new viruses), but also in this situation the cccDNA will remain in the liver cells. how this will be manage?
Can we assume that because we don't have s and e antigens the immune system will target the infected liver cells and destroy them ?
That is the basic concept. In addition to the direct targeting by cd8 cytotoxic Tcells, the local phagocytosis of virions and debris from necrotic liver cells containing HBV proteins will allow presentation of the classII peptide epitopes on the surface of Macrophages and Kupffer cells to cd4 helperTcells in the liver, with a strong local cytokine response that will help in the noncytolytic clearance of hepatocytes fromm HBVcccDNA.
One problem is likely that the longstanding exhaustion of the s antigen specific T-cell clone repertoire (many many years of periphery flooding with e and s antigens) will require a substantial time frame of regeneration of this immune response, particularly in older patients and those with a longer chronic infection. Thus a longer supression of s-antigen release by REp 9AC might be necessary to allow targeted immune recovery in these patients.
Aside from protection against adaptive immune evasive epitope mutations by antivirals, it might also be advisable to accelerate the regeneration of the blunted adaptive immune response - TandB cells- by therapeutic vaccinations once the s-antigen is negative.
Regarding new developments on the horizon, there is a therapeutic HBV vaccine by Dynavax, that could be used eg in the context above. Replicor and Myrcludex remain the most promising partial attack modes against HBV at this moment.
The liver concentrating tenofovir would be a great element of progress, since reduction in antiviral toxicity is a major concern, consdering the need for long term use.
Nitazoxanide thus far - see Stefs progress reports- seems to be of weak effectiveness, at least at the dosing that is low enough for comfort.
Substances like squalamine might be virus propagation blocking to a certain degree, but the effect on the reduction of the cccDNA hepatocyte population is unlikely to be better than the one with antivirals. It is too early to make any specific predictions.作者: StephenW 时间: 2011-9-27 14:02
Rep9AC will suppress HBsAg and in this case we can produce HBsAb ? and what happen if ccDNA will remain in some liver cells ? will be enough HBsAb to suppress HBsAg after the Rep9Ac treatment is stooped ? .
Providing that enough s antigen specific B cells are left or have recovered, there will be an antiHbs antibody titer.
If, after REP9AC is stopped only a tiny amount of infected cccDNA containing cells are left after immune clearance, then the antibody will be sufficient to neutralize this very very small amount of surface antigen.
The key is the suffcient reduction of the cccDNA containing hepatocye pool PLUS a remaining population of HBV antigen specific Tcells in the liver to help supress the synthetic and replicative activity of this small cell pool by a local permanent cytokine milieu, that will inhibit transcription , replication and possibly translation of the HBVgenomes that will still reside in the liver, just as is the case with persons with acute recovered Hepatitis B - for a lifetime, without outside intervention.
It needs to be understood, that the antiHbS antibody is only protecting against reinfection. The key long term controlling factor is a long lasting antigen specific Tcell response residing in the liver.
Only in case of a cancer chemotherapy or intense antinflammatory therapy with TNFalpha inhibitors such remnant HBV clusters tend to regrow and reactivate, since the permanent watchdog forces are now of diminshed activty - a process called REACTIVATION. It is now becoming routine to protect against such reactivations in prior acute recovered HBV cases or chronic cleared HBSseroconverters with temporary antivirals during such treatments. 作者: cwy121 时间: 2011-9-27 14:10
Myrcludex presentation at the San Francisco liver conference.
Conclusions: Myrcludex-B showed strong capacities to prevent HBV spreading in vivo. Since maintenance of chronic HBV infection involves a dynamic turnover between cells that are cleared by the immune system and cells that become newly infected, the use of drugs preventing hepatocyte re-infection, possibly in combination with other HBV-drugs, may represent a new effective antiviral concept also in the setting of chronic infection.
Myrcludex blocks the entry of HBv into hepatocytes. That is all it does. Over time, that should indirectly reduce the pool of infected cells, by whatever means this reduction is operative, mainly the ongoing erosive immune attack, that causes the ALTs to be elevated. The question is really right now, how effective will the planned dose of Myrcludex of 1mg/day be in achieving this effect.
If the reduction of infected cells and therefore the cccDNA has come down to a level, where the surface antigen disappears from the circulation, then permanent immune control of the infection is likely, even after stopping myrcludex.
Myrcludex and Replicor would beautifully complement each other, since the effects are on entirely different aspects of the viral mechanisms.
Replicor blocks the release of the surface antigen particle from infected hepatocytes, not of any virions. It does that with great reliability and apparently very little side effects.
That effect per se however is not blocking the virus from replicating or directly reduces the cccDNA. What happens now is that the removal of the surface antigen allows the immune system to focus its anti surface effector cells on the liver and that will lead to an increased removal of infected cells, plus reduction in viral replication and transcription by noncytolytic mechanisms and ,unless the virus is able to respond evasivly, to a reduction of the infected cell number and the cccDNA to a level where permanent immune control of the remnant amounts will be possible, without outside medications.
Myrcludex would help in the speed of this process by preventing reinfection, speeding up clearance and, quite importantly, prevent any immunologically resistant subpopulation from spreading, thus ensuring the success of the REP9A treatment.
About the MYR GmbH The company located in Burgwedel near Hannover was founded in 2010 and holds the world-wide exclusive product rights for Myrcludex. Currently, the company has 2 employees who are focused on the coordination of the network of academic partners and vendors involved in the Myrcludex development. Dr. Alexander Alexandrov, MYR CSO: „We have established a very successful public-private partnership giving birth to a promising and efficient Biotech-company“.
投资公司Gründerfonds About High-Tech Gründerfonds
High-Tech Gründerfonds invests venture capital in promising technology companies that turn innovative concepts into viable businesses. Seed financing aims to help start-ups guide their innovation to the prototype or proof-of-concept stage or to market launch. High-Tech Gründerfonds provides seed financing of approximately €500,000. It supports high-tech companies by way of its investment managers and its highly-qualified network of coaches, investors and specialists. In individual cases it can invest up to a total of €2 m per company. The investors in this public private partnership are the German Federal Ministry for Business and Technology, the KfW Banking Group as well as the six industrial groups of BASF, Deutsche Telekom, Siemens, Robert Bosch, Daimler and Carl Zeiss. High-Tech Gründerfonds has an investment volume totalling approx. €272 m. 作者: kaorusai 时间: 2011-10-3 18:14
Myrcludex演示文稿 - 旧金山, 肝病学会2011
[posted by studyforhope]
Myrcludex presentation at the San Francisco liver conference.
The entry inhibitor Myrcludex-B efficiently blocks viral spreading in vivo in human liver chimeric uPA/SCID mice previously infected with Hepatitis B Virus
M. Lutgehetmann1, 2; J. Petersen3; T. Volz1; L. Allweiss1; A. W. Lohse1; S. Urban4; M. Dandri1
1. Internal Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany.
2. Medical Microbiology, University Hospital Hamburg Eppendorf, Hamburg, Germany.
3. Asklepiosklinik St. Georg, Liver Center Hamburg IFI Institute, Hamburg, Germany.
4. Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany.
Currently approved antiviral treatments based on interferon alpha or inhibitors of the hepatitis B virus (HBV) polymerase are generally not curative and additional therapeutic strategies interfering with other HBV replication steps are needed. We previously demonstrated prevention of de novo HBV infection by pre-treating uPA mice with Myrcludex-B, a lipopeptide derived from the preS1 domain of the HBV envelope (Nat. Biotech.2008). Aim of this study was to investigate the ability of this HBV entry inhibitor to block viral spreading post-infection, at a time when viremia is already detectable but only few human hepatocytes are infected. Experimental design: human liver chimeric uPA/SCID mice were injected with HBV-infectious serum (5x10E7 HBV DNA copies/mouse) and treatment with Myrcludex-B (2 mg/Kg/day; s.c. injection) was initiated either 3 days (group A, n=8) or 3 weeks (group B, n=7) post HBV-inoculation, while 8 sham-treated mice were used as control. Mice were analyzed serologically (HBV-DNA, HBsAg) and intrahepatically by quantitative RT-PCR measurements (cccDNA) and immunohistochemistry (human CK-18, HBcAg) at baseline, after 3 and 6 weeks of treatment. Results: In the first experimental setting, Myrcludex-B administration initiated 3-days after HBV-inoculation efficiently prevented viral spreading from the few initially infected human hepatocytes, as demonstrated by immunohistochemistry. Viremia and HBsAg levels remained below 10E5 HBV-DNA/ml and <10 IU/ml, respectively, while in untreated control mice median viremia increased to 3x10E7 and the majority of human hepatocytes stained HBcAg-positive within six weeks post-infection. Occurrence of viral spreading was also demonstrated in 2 mice after therapy discontinuation. Furthermore, Myrcludex-B blocked viral spreading even when treatment was first initiated at 3-weeks post-infection, at a time when median viremia was 2x10E6 HBV-DNA/ml. Notably, levels of viremia, HBsAg and intrahepatic cccDNA loads did not increase significantly after 6 weeks of treatment. Conclusions: Myrcludex-B showed strong capacities to prevent HBV spreading in vivo. Since maintenance of chronic HBV infection involves a dynamic turnover between cells that are cleared by the immune system and cells that become newly infected, the use of drugs preventing hepatocyte re-infection, possibly in combination with other HBV-drugs, may represent a new effective antiviral concept also in the setting of chronic infection. 作者: StephenW 时间: 2011-10-8 03:24
REP 9AC论文摘要 - 旧金山, 肝病学会2011
[posted by studyforhope]
Here is the current abstract for REP9AC at the upcoming San Francisco AASLD liver conference 2011:
REP 9AC: A potent HBsAg release inhibitor that elicits durable immunological control of chronic HBV infection.
M. A. Mahtab2; M. Bazinet1; A. Vaillant1
1. REPLICor Inc., Montreal, QC, Canada.
2. Bangabandhu Sheikh Mujib University, Dhaka, Bangladesh.
BACKGROUND: HBsAg plays a critical role in suppressing the immune system and is the likely mechanism for the chronicity of HBV infection. REP 9AC is a nucleic acid-based amphipathic polymer (NAP) which inhibits the release of HBsAg from infected hepatocytes. Previous interim clinical data has shown that REP 9AC rapidly clears serum HBsAg in infected patients and allows patients to regain durable immunological control over their HBV infection. An updated progress report of the ongoing phase I/II study on the safety and efficacy of REP 9AC in patients with chronic HBV (CHB) infection is presented.
METHODS: All patients were HBsAg+ with pre-treatment HBV DNA titers between 106 and 1012 copies/ml. Additionally, all patients were shown to have significant liver fibrosis as assessed by pre-treatment liver biopsy. Patients with CHB were subjected to parenteral REP 9AC therapy. Safety and virologic response (HBV DNA [Roche Cobas ™], HBsAg, anti-HBs [Immunilite]) were assessed weekly at the trial site/. Off site confirmatory testing of HBsAg, HBeAg, anti-HBs, anti-HBe was conducted using the using the Architect ™ platform.
RESULTS: Interim data shows that 7 out of 8 patients treated to date have either cleared or have only residual levels of serum HBsAg and anti-HBsAg antibodies have been observed in all patients. Clearance of HBsAg and development of anti-HBs have been observed as early as 7 days and no later than 32 weeks. At the time of abstract submission, 6 out of 7 patients with serum HBsAg reductions had achieved a 3 to 7 log reduction in their HBV DNA titers from pre-treatment levels after 7-13 weeks of treatment. Additionally, three of these seven patients have achieved a complete control of their infection with 20-27 weeks of treatment (HBV DNA < 400cpm-, HBsAg -, HBeAg -, anti-HBs +, anti-HBe +) and are being followed off treatment. These three patients have demonstrated durable immunological control over their infections, having SVRs of 18 months, 12 months and 10.5 months after cessation of treatment.
CONCLUSIONS: These results demonstrate that REP 9AC can rapidly and effectively clear HBsAg from the serum of infected patients. This rapid HBsAg seroclearance appears to allow the restoration of an effective immune response, as evidenced by substantial reductions in serum HBV DNA, seroconversion for HBsAg and HBeAg, and the achievement of SVRs in three patients to date. These results suggest that REP 9AC may become an important new tool in the treatment of chronic hepatitis B. 作者: 潇洒书生 时间: 2011-10-8 13:10